Heterocyclic compounds

ABSTRACT

The present invention relates to substituted heteroaromatic compounds, methods for their preparation, pharmaceutical compositions containing them and their use in medicine. Specifically, the invention relates to quinazoline derivatives useful in treating disorders mediated by protein tyrosine kinase activity, in particular erbB-2 and/or EGFR activity.

[0001] The present invention relates to a series of substitutedheteroaromatic compounds, methods for their preparation, pharmaceuticalcompositions containing them and their use in medicine. In particular,the invention relates to quinoline, quinazoline, pyridopyridine andpyridopyrimidine derivatives which exhibit protein tyrosine kinaseinhibition.

[0002] Protein tyrosine kinases catalyse the phosphorylation of specifictyrosyl residues in various proteins involved in the regulation of cellgrowth and differentiation (A. F. Wilks, Progress in Growth FactorResearch, 1990, 2, 97-111; S. A. Courtneidge, Dev. Supp.I, 1993, 57-64;J. A. Cooper, Semin. Cell Biol., 1994, 5(6), 377-387; R. F. Paulson,Semin. Immunol., 1995, 7(4), 267-277; A. C. Chan, Curr. Opin. Immunol.,1996, 8(3), 394-401). Protein tyrosine kinases can be broadly classifiedas receptor (e.g. EGFr, c-erbB-2, c-met, tie-2, PDGFr, FGFr) ornon-receptor (e.g. c-src, Ick, zap70) kinases. Inappropriate oruncontrolled activation of many of these kinase, i.e. aberrant proteintyrosine kinase activity, for example by over-expression or mutation,has been shown to result in uncontrolled cell growth.

[0003] Aberrant activity of protein tyrosine kinases, such as c-erbB-2,c-src, c-met, EGFr and PDGFr have been implicated in human malignancies.Elevated EGFr activity has, for example, been implicated in non-smallcell lung, bladder and head and neck cancers, and increased c-erbB-2activity in breast, ovarian, gastric and pancreatic cancers. Inhibitionof protein tyrosine kinases should therefore provide a treatment fortumours such as those outlined above.

[0004] Aberrant protein tyrosine kinase activity has also beenimplicated in a variety of other disorders: psoriasis, (Dvir et al, J.Cell. Biol; 1991, 113, 857-865), fibrosis, atherosclerosis, restenosis,(Buchdunger et al, Proc. Natl. Acad. Sci. USA; 1991, 92, 2258-2262),auto-immune disease, allergy, asthma, transplantation rejection(Klausner and Samelson, Cell; 1991, 64, 875-878), inflammation (Berkois,Blood; 1992, 79(9), 2446-2454), thrombosis (Salari et al, FEBS;1990,263(1), 104-108) and nervous system diseases (Ohmichi et al,Biochemistry, 1992, 31, 4034-4039). Inhibitors of the specific proteintyrosine kinases involved in these diseases eg PDGF-R in restenosis andEGF-R in psoriasis, should lead to novel therapies for such disorders.P56lck and zap 70 are indicated in disease conditions in which T cellsare hyperactive e.g. rheumatoid arthritis, autoimmune disease, allergy,asthma and graft rejection. The process of angiogenesis has beenassociated with a number of disease states (e.g. tumourogenesis,psoriasis, rheumatoid arthritis) and this has been shown to becontrolled through the action of a number of receptor tyrosine kinases(L. K. Shawver, DDT, 1997, 2(2), 50-63).

[0005] It is therefore a general object of the present invention toprovide compounds suitable for the treatment of disorders mediated byprotein tyrosine kinase activity, and in particular treatment of theabove mentioned disorders.

[0006] In addition to the treatment of tumours, the present inventionenvisages that other disorders mediated by protein tyrosine kinaseactivity may be treated effectively by inhibition, includingpreferential inhibition, of the appropriate protein tyrosine kinaseactivity.

[0007] Broad spectrum inhibition of protein tyrosine kinase may notalways provide optimal treatment of, for example tumours, and could incertain cases even be detrimental to subjects since protein tyrosinekinases provide an essential role in the normal regulation of cellgrowth.

[0008] It is another object of the present invention to providecompounds which preferentially inhibit protein tyrosine kinases, such asEGFr, c-erbB-2, c-erbB-4, c-met, tie-2, PDGFr, c-src, Ick, Zap70, andfyn. There is also perceived to be a benefit in the preferentialinhibition involving small groups of protein tyrosine kinases, forexample groups including two or more of c-erbB-2, c-erbB-4, EGF-R, Ickand zap70.

[0009] A further object of the present invention is to provide compoundsuseful in the treatment of protein tyrosine kinase related diseaseswhich minimise undesirable side-effects in the recipient.

[0010] The present invention relates to heterocyclic compounds which maybe used to treat disorders mediated by protein tyrosine kinases and inparticular have anti-cancer properties. More particularly, the compoundsof the present invention are potent inhibitors of protein tyrosinekinases such as such as EGFr, c-erbB-2, c-erbB-4, c-met, tie-2, PDGFr,c-src, lck, Zap70, and fyn, thereby allowing clinical management ofparticular diseased tissues.

[0011] The present invention envisages, in particular, the treatment ofhuman malignancies, for example breast, non-small cell lung, ovary,stomach, and pancreatic tumours, especially those driven by EGF-R orerbB-2, using the compounds of the present invention. For example, theinvention includes compounds which are highly active against thec-erbB-2 protein tyrosine kinase often in preference to the EGF receptorkinase hence allowing treatment of c-erbb-2 driven tumours. However, theinvention also includes compounds which are highly active against bothc-erbB-2 and EGF-R receptor kinases hence allowing treatment of abroader range of tumours.

[0012] The present invention also includes compounds which are activeagainst Ick and/or zap70 receptor kinases; these may also be activeagainst c-erbB-2 and/or EGF-R receptor kinases. The compounds may beselective towards Ick and/or zap70 in comparison to c-erbB-2 and/orEGF-R.

[0013] More particularly, the present invention envisages that disordersmediated by protein tyrosine kinase activity may be treated effectivelyby inhibition of the appropriate protein tyrosine kinase activity in arelatively selective manner, thereby minimising potential side effects.

[0014] Accordingly, the present invention provides a compound of formula(I)

[0015] or a salt or solvate thereof;

[0016] wherein X is N or CH;

[0017] Y is CR¹ and V is N;

[0018] or Y is N and V is CR¹;

[0019] or Y is CR¹ and V is CR²;

[0020] or Y is CR² and V is CR¹;

[0021] R¹ represents a group CH₃SO₂CH₂CH₂NHCH₂—Ar—, wherein Ar isselected from phenyl, furan, thiophene, pyrrole and thiazole, each ofwhich may optionally be substituted by one or two halo, C₁₋₄ alkyl orC₁₋₄ alkoxy groups;

[0022] R² is selected from the group comprising hydrogen, halo, hydroxy,C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino and di[C₁₋₄ alkyl]amino;

[0023] U represents a phenyl, pyridyl, 3H-imidazolyl, indolyl,isoindolyl, indolinyl, isoindolinyl, 1H-indazolyl,2,3-dihydro-1H-indazolyl, 1H-benzimidazolyl,2,3-dihydro-1H-benzimidazolyl or 1H-benzotriazolyl group, substituted byan R³ group and optionally substituted by at least one independentlyselected R⁴ group;

[0024] R³ is selected from a group comprising benzyl, halo-, dihalo- andtrihalobenzyl, benzoyl, pyridylmethyl, pyridylmethoxy, phenoxy,benzyloxy, halo-, dihalo- and trihalobenzyloxy and benzenesulphonyl;

[0025] or R³ represents trihalomethylbenzyl or trihalomethylbenzyloxy;

[0026] or R³ represents a group of formula

[0027] wherein each R⁵ is independently selected from halogen, C₁₋₄alkyl and C₁₋₄ alkoxy; and n is 0 to 3;

[0028] each R⁴ is independently hydroxy, halogen, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, amino, C₁₋₄ alkylamino, di[C₁₋₄alkyl]amino, C₁₋₄ alkylthio, C₁₋₄ alkylsulphinyl, C₁₋₄ alkylsulphonyl,C₁₋₄ alkylcarbonyl, carboxy, carbamoyl, C₁₋₄ alkoxycarbonyl, C₁₋₄alkanoylamino, N-(C₁₋₄ alkyl)carbamoyl, N,N-di(C₁₋₄ alkyl)carbamoyl,cyano, nitro and trifluoromethyl;

[0029] with the proviso that the following compounds are excluded:

[0030](1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl-amine;

[0031](4-Benzyloxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl-amine;

[0032](1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl-amine;

[0033](1-Benzyl-1H-indazol-5-yl)-(7-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl-amine;

[0034](1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-1-methyl-pyrrol-2-yl)-quinazolin-4-yl-amine;

[0035] and their hydrochloride salts.

[0036] Solvates of the compounds of formula (I) are also included withinthe scope of the present invention.

[0037] The definitions for X, Y and V thus give rise to a number ofpossible basic ring systems for the compounds of formula (I). Inparticular the compounds may contain the following basic ring systems:

[0038] It will be seen that for compounds containing the basic ringsystem (1) the group R¹ may be at the 6- or 7-position; the compounds inwhich R¹ is in the 7-position are of particular interest in the contextof Ick and/or zap70 activity.

[0039] It will be seen that for compounds containing the basic ringsystem (2) the group R¹ may be at the 6- or 7-position; the compounds inwhich R¹ is in the 6-position are of particular interest in the contextof c-erbB-2 activity whereas the compounds in which R¹ is in the7-position are of particular interest in the context of Ick and/or zap70activity.

[0040] Ring systems (1), (2), (5) and (6) are preferred; ring systems(2) and (6) are more preferred.

[0041] Ring system (1) is also more preferred.

[0042] Alkyl groups containing three or more carbon atoms may bestraight, branched or cyclised; preferably they are straight orbranched. References to a specific alkyl group such as “butyl” isintended to refer to the straight chain (n-) isomer only. References toother generic terms such as alkoxy, alkylamino etc. are to beinterpreted analogously.

[0043] Suitable values for the various groups listed above within thedefinitions for R¹, R², R⁴ and R⁵ are as follows:

[0044] halo is, for example, fluoro, chloro, bromo or iodo; preferablyit is fluoro, chloro or bromo, more preferably fluoro or chloro;

[0045] C₁₋₄ alkyl is, for example, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl or tert-butyl; preferably it is methyl,ethyl, propyl, isopropyl or butyl, more preferably methyl;

[0046] C₂₋₄ alkenyl is, for example, ethenyl, prop-1-enyl orprop-2-enyl; preferably it is ethenyl;

[0047] C₂₋₄ alkynyl is, for example, ethynyl, prop-1-ynyl orprop-2-ynyl; preferably it is ethynyl;

[0048] C₁₋₄ alkoxy is, for example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; preferablyit is methoxy, ethoxy, propoxy, isopropoxy or butoxy; more preferably itis methoxy;

[0049] C₁₋₄ alkylamino is, for example, methylamino, ethylamino orpropylamino; preferably it is methylamino;

[0050] di[C₁₋₄ alkyl]amino is, for example, dimethylamino, diethylamino,N-methyl-N-ethylamino or dipropylamino; preferably it is dimethylamino;

[0051] C₁₋₄ alkylthio is, for example, methylthio, ethylthio, propylthioor isopropylthio, preferably methylthio;

[0052] C₁₋₄ alkylsulphinyl is, for example, methylsulphinyl,ethylsulphinyl, propylsulphinyl or isopropylsulphinyl, preferablymethylsulphinyl;

[0053] C₁₋₄ alkylsulphonyl is, for example, methanesulphonyl,ethylsulphonyl, propylsulphonyl or isopropylsulphonyl, preferablymethanesulphonyl;

[0054] C₁₋₄ alkylcarbonyl is, for example methylcarbonyl, ethylcarbonylor propylcarbonyl;

[0055] C₁₋₄ alkoxycarbonyl is, for example, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl or tert-butoxycarbonyl;

[0056] C₁₋₄ alkanoylamino (where the number of carbon atoms includes theCO functionality) is, for example, formamido, acetamido, propionamido orbutyramido;

[0057] N-(C₁₋₄ alkyl)carbamoyl is, for example, N-methylcarbamoyl orN-ethylcarbamoyl;

[0058] N,N-di(C₁₋₄ alkyl)carbamoyl is, for example,N,N-dimethylcarbamoyl, N-methyl-N-ethylcarbamoyl orN,N-diethylcarbamoyl.

[0059] In an especially preferred embodiment X is N, Y is CR¹ and V isCR² (ring system (2) above).

[0060] In a further especially preferred embodiment X is N, Y is CR² andV is CR¹ (ring system (2) above).

[0061] In a further especially preferred embodiment X is N, Y is CR¹ andV is N (ring system (6) above).

[0062] In a preferred embodiment R² represents hydrogen or C₁₋₄ alkoxy.

[0063] In a more preferred embodiment R² represents hydrogen or methoxy.

[0064] In a further preferred embodiment R² represents halo; morepreferred R² is fluoro.

[0065] In a preferred embodiment the group Ar is substituted by onehalo, C₁₋₄ alkyl or C₁₋₄ alkoxy group.

[0066] In a more preferred embodiment the group Ar is substituted by aC₁₋₄ alkyl group.

[0067] In a further more preferred embodiment the group Ar does notcarry any optional substituents.

[0068] In a further more preferred embodiment Ar represents furan,phenyl or thiazole, each of which may optionally be substituted asindicated above.

[0069] In a further more preferred embodiment Ar represents furan orthiazole, each of which may optionally be substituted as indicatedabove.

[0070] In a most preferred embodiment Ar represents unsubstituted furanor thiazole.

[0071] The side chain CH₃SO₂CH₂CH₂NHCH₂ may be linked to any suitableposition of the group Ar. Similarly, the group R¹ may be linked to thecarbon atom carrying it from any suitable position of the group Ar.

[0072] In a preferred embodiment, when Ar represents furan the sidechain CH₃SO₂CH₂CH₂NHCH₂ is in the 4-position of the furan ring and thelink to the carbon atom carrying the group R¹ is from the 2-position ofthe furan ring.

[0073] In another preferred embodiment, when Ar represents furan theside chain CH₃SO₂CH₂CH₂NHCH₂ is in the 3-position of the furan ring andthe link to the carbon atom carrying the group R¹ is from the 2-positionof the furan ring.

[0074] In a most preferred embodiment, when Ar represents furan the sidechain CH₃SO₂CH₂CH₂NHCH₂ is in the 5-position of the furan ring and thelink to the carbon atom carrying the group R¹ is from the 2-position ofthe furan ring.

[0075] In a further most preferred embodiment, when Ar representsthiazole the side chain CH₃SO₂CH₂CH₂NHCH₂ is in the 2-position of thethiazole ring and the link to the carbon atom carrying the group R¹ isfrom the 4-position of the thiazole ring.

[0076] The R³ and R⁴ groups may be bound to the ring system U by eithera carbon atom or a heteroatom of the ring system. The ring system itselfmay be bound to the bridging NH group by a carbon atom or a heteroatombut is preferably bound by a carbon atom. The R³ and R⁴ groups may bebound to either ring when U represents a bicyclic ring system, but thesegroups are preferably bound to the ring which is not bound to thebridging NH group in such a case.

[0077] In a preferred embodiment U represents a phenyl, indolyl, or1H-indazolyl group substituted by an R³ group and optionally substitutedby at least one independently selected R⁴ group.

[0078] In a more preferred embodiment U represents a phenyl or1H-indazolyl group substituted by an R³ group and optionally substitutedby at least one independently selected R⁴ group.

[0079] In a more preferred embodiment, where U represents a phenyl groupthe group R³ is in the para- position relative to the bond from U to thelinking NH group.

[0080] In a further more preferred embodiment, where U represents a1H-indazolyl group the group R³ is in the 1-position of the indazolylgroup.

[0081] In a preferred embodiment R³ represents benzyl, pyridylmethyl,phenoxy, benzyloxy, halo-, dihalo- and trihalobenzyloxy andbenzenesulphonyl.

[0082] In a further preferred embodiment R³ representstrihalomethylbenzyloxy.

[0083] In a further preferred embodiment R³ represents a group offormula

[0084] wherein Hal is Br or Cl, particularly Cl, more especially whereinthe Hal substituent is in the position marked with a star in the ring asshown.

[0085] In a more preferred embodiment R³ represents benzyloxy,fluorobenzyloxy (especially 3-fluorobenzyloxy), benzyl, phenoxy andbenzenesulphonyl.

[0086] In a further more preferred embodiment R³ representsbromobenzyloxy (especially 3-bromobenzyloxy) andtrifluoromethylbenzyloxy.

[0087] In a further preferred embodiment the ring U is not substitutedby an R⁴ group; in an especially preferred embodiment U is phenyl orindazolyl unsubstituted by an R⁴ group.

[0088] In a further preferred embodiment the ring U is substituted by anR⁴ group selected from halo or C₁₋₄ alkoxy; especially chloro, fluoro ormethoxy.

[0089] In a more preferred embodiment the ring U is substituted by an R⁴group wherein R⁴ represents halo, especially 3-fluoro.

[0090] In an especially preferred embodiment U together with R⁴represents methoxyphenyl, fluorophenyl, trifluoromethylphenyl orchlorophenyl.

[0091] In a more especially preferred embodiment U together with R⁴represents methoxyphenyl or fluorophenyl.

[0092] In an especially preferred embodiment the group U together withthe substituent(s) R³ and R⁴ represents benzyloxyphenyl,(fluorobenzyloxy)phenyl, (benzenesulphonyl)phenyl, benzylindazolyl orphenoxyphenyl.

[0093] In a more especially preferred embodiment the group U togetherwith the substituent(s) R³ and R⁴ represents benzyloxyphenyl,(3-fluorobenzyloxy)phenyl, (benzenesulphonyl)phenyl or benzylindazolyl.

[0094] In another more especially preferred embodiment the group Utogether with the substituent(s) R³ and R⁴ represents(3-bromobenzyloxy)phenyl, (3-trifluoromethylbenzyloxy)phenyl, or(3-fluorobenzyloxy)-3-methoxyphenyl.

[0095] In another more especially preferred embodiment the group Utogether with the substituent(s) R³ and R⁴ represents3-fluorobenzyloxy-3-chlorophenyl, benzyloxy-3-chlorophenyl,benzyloxy-3-trifluoromethylphenyl, (benzyloxy)-3-fluorophenyl,(3-fluorobenzyloxy)-3-fluorophenyl or (3-fluorobenzyl)indazolyl.

[0096] In a most especially preferred embodiment the group U togetherwith the substituent(s) R³ and R⁴ represents benzyloxyphenyl or(3-fluorobenzyloxy)phenyl.

[0097] In a preferred embodiment there is provided a compound of formula(I) or a salt or solvate thereof wherein X is N; V is CR², wherein R² ishydrogen, halo (especially fluoro) or C₁₋₄ alkoxy (especially methoxy);Y is CR¹ wherein R¹ is as defined above in which Ar is unsubstitutedphenyl, furan or thiazole; U is phenyl or indazole; R³ is benzyl,fluorobenzyl, benzyloxy, fluorobenzyloxy, bromobenzyloxy,trifluoromethylbenzyloxy, phenoxy or benzenesulphonyl; and R⁴ is notpresent or is halo (especially chloro or fluoro), or methoxy.

[0098] In a most preferred embodiment there is provided a compound offormula (I) or a salt or solvate thereof wherein X is N; V is CR²,wherein R² is hydrogen, halo (especially fluoro) or C₁₋₄ alkoxy(especially methoxy); Y is CR¹ wherein R¹ is as defined above in whichAr is unsubstituted furan or thiazole; U is phenyl; R³ is benzyloxy,fluorobenzyloxy or benzenesulphonyl; and R⁴ is not present or is halo(especially chloro or fluoro), or methoxy.

[0099] In a most preferred embodiment there is provided a compound offormula (I) or a salt or solvate thereof wherein X is N; V is CR²,wherein R² is hydrogen, halo (especially fluoro) or C₁₋₄ alkoxy(especially methoxy); Y is CR¹ wherein R¹ is as defined above in whichAr is unsubstituted furan or thiazole; U is indazole; R³ is benzyl orfluorobenzyl; and R⁴ is not present.

[0100] In a further more preferred embodiment there is provided acompound of formula (I) or a salt or solvate thereof wherein X is N; Yis CR², wherein R² is hydrogen, halo (especially fluoro) or C₁₋₄ alkoxy(especially methoxy); V is CR¹ wherein R¹ is as defined above in whichAr is unsubstituted phenyl, furan or thiazole; U is phenyl or indazole;R³ is benzyl, fluorobenzyl, benzyloxy, fluorobenzyloxy, bromobenzyloxy,trifluoromethylbenzyloxy, phenoxy or benzenesulphonyl; and R⁴ is notpresent or is halo (especially chloro or fluoro), or methoxy.

[0101] In a further most preferred embodiment there is provided acompound of formula (I) or a salt or solvate thereof wherein X is N; Yis CR², wherein R² is hydrogen, halo (especially fluoro) or C₁₋₄ alkoxy(especially methoxy); V is CR¹ wherein R¹ is as defined above in whichAr is unsubstituted furan or thiazole; U is phenyl; R³ is benzyloxy,fluorobenzyloxy or benzenesulphonyl; and R⁴ is not present or is halo(especially chloro or fluoro), or methoxy.

[0102] In a further most preferred embodiment there is provided acompound of formula (I) or a salt or solvate thereof wherein X is N; Yis CR², wherein R² is hydrogen, halo (especially fluoro) or C₁₋₄ alkoxy(especially methoxy); V is CR¹ wherein R¹ is as defined above in whichAr is unsubstituted furan or thiazole; U is indazole; R³ is benzyl orfluorobenzyl; and R⁴ is not present.

[0103] In a most especially preferred embodiment there is provided acompound of formula(I) or a salt or solvate thereof wherein X is N, Y isCR², wherein R² is hydrogen, halo (especially fluoro) or C₁₋₄ alkoxy(especially methoxy); V is CR¹ wherein R¹ is as defined above in whichAr is unsubstituted furan or thiazole; U is phenyl; R³ is phenoxy; andR⁴ is not present.

[0104] In another more preferred embodiment there is provided a compoundof formula (I) or a salt or solvate thereof wherein X is N; V is N; Y isCR¹ wherein R¹ is as defined above in which Ar is unsubstituted phenyl,furan or thiazole; U is phenyl or indazole; R³ is benzyl, fluorobenzyl,benzyloxy, fluorobenzyloxy, bromobenzyloxy, trifluoromethylbenzyloxy,phenoxy or benzenesulphonyl; and R⁴ is not present or is halo(especially chloro or fluoro), or methoxy.

[0105] In another most preferred embodiment there is provided a compoundof formula (I) or a salt or solvate thereof wherein X is N; V is N, Y isCR¹ wherein R¹ is as defined above in which Ar is unsubstituted furan orthiazole; U is phenyl; R³ is benzyloxy, fluorobenzyloxy orbenzenesulphonyl; and R⁴ is not present or is halo (especially chloro orfluoro), or methoxy.

[0106] In another most preferred embodiment there is provided a compoundof formula (I) or a salt or solvate thereof wherein X is N; V is N, Y isCR¹ wherein R¹ is as defined above in which Ar is unsubstituted furan orthiazole; U is indazole; R³ is benzyl or fluorobenzyl; and R⁴ is notpresent.

[0107] In yet another preferred embodiment there is provided a compoundof formula (I) or a salt or solvate thereof wherein X is CH; Y is CR²,wherein R² is hydrogen, halo (especially fluoro) or C₁₋₄ alkoxy(especially methoxy); V is CR¹ wherein R¹ is as defined above in whichAr is unsubstituted phenyl, furan or thiazole; U is phenyl or indazole;R³ is benzyl, fluorobenzyl, benzyloxy, fluorobenzyloxy, bromobenzyloxy,trifluoromethylbenzyloxy, phenoxy or benzenesulphonyl; and R⁴ is notpresent or is halo (especially chloro or fluoro), or methoxy.

[0108] In yet another most preferred embodiment there is provided acompound of formula (I) or a salt or solvate thereof wherein X is CH; Yis CR², wherein R² is hydrogen, halo (especially fluoro) or C₁₋₄ alkoxy(especially methoxy); V is CR¹ wherein R¹ is as defined above in whichAr is unsubstituted furan or thiazole; U is phenyl; R³ is benzyloxy,fluorobenzyloxy, phenoxy or benzenesulphonyl; and R⁴ is not present oris halo (especially chloro or fluoro), or methoxy.

[0109] In yet another most preferred embodiment there is provided acompound of formula (I) or a salt or solvate thereof wherein X is CH; Yis CR², wherein R² is hydrogen, halo (especially fluoro) or C₁₋₄ alkoxy(especially methoxy); V is CR¹ wherein R¹ is as defined above in whichAr is unsubstituted furan or thiazole; U is indazole; R³ is benzyl orfluorobenzyl; and R⁴ is not present.

[0110] In a most especially preferred embodiment there is provided acompound of formula(I) or a salt or solvate thereof wherein X is CH, Yis CR², wherein R² is hydrogen, halo (especially fluoro) or C₁₋₄ alkoxy(especially methoxy); V is CR¹ wherein R¹ is as defined above in whichAr is unsubstituted furan or thiazole; U is phenyl; R³ is phenoxy; andR⁴ is not present.

[0111] Preferred compounds of the present invention include:

[0112]4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0113](4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0114] (4-Benzenesulphonyl-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0115](4-Benzyloxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0116](4-Benzyloxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine;

[0117] (4-(3-Fluorobenzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0118](4-Benzyloxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;

[0119]N-{4-[(3-Fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0120]N-{4-[(3-Fluorobenzyl)oxy]-3-methoxyphenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0121]N-[4-(Benzyloxy)phenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0122] N-[4-(Benzyloxy)phenyl]-6-[4-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0123]N-{4-[(3-Fluorobenzyl)oxy]-3-methoxyphenyl}-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0124]N-{4-[(3-Bromobenzyl)oxy]phenyl}-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0125]N-{4-[(3-Fluorobenzyl)oxy]phenyl}-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0126]N-[4-(Benzyloxy)-3-fluorophenyl]-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0127]N-(1-Benzyl-1H-indazol-5-yl)-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0128]6-[5-({[2-(Methanesulphonyl)ethyl]amino}methyl)-2-furyl]-N-(4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)-4-quinazolinamine;

[0129]N-{3-Fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0130]N-{4-[(3-Bromobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0131]N-[4-(Benzyloxy)phenyl]-6-[3-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0132]N-[1-(3-Fluorobenzyl)-1H-indazol-5-yl]-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0133]6-[5-({[2-(Methanesulphonyl)ethyl]amino}methyl)-2-furyl]-N-[4-(benzenesulphonyl)phenyl]-4-quinazolinamine;

[0134]6-[2-({[2-(Methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-N-[4-(benzenesulphonyl)phenyl]-4-quinazolinamine;

[0135]6-[2-({[2-(Methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-N-(4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)-4-quinazolinamine

[0136]N-{3-Fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0137]N-(1-Benzyl-1H-indazol-5-yl)-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0138]N-(3-Fluoro-4-benzyloxyphenyl)-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0139]N-(3-Chloro-4-benzyloxyphenyl)-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0140]N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0141]6-[5-({[2-(Methanesulphonyl)ethyl]amino}methyl)-2-furyl]-7-methoxy-N-(4-benzenesulphonyl)phenyl-4-quinazolinamine;

[0142]N-[4-(Benzyloxy)phenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0143]N-(1-Benzyl-1H-indazol-5-yl)-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0144]N-[4-(Benzenesulphonyl)phenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino)methyl)-2-furyl]-4-quinazolinamine;

[0145]N-(3-Trifluoromethyl-4-benzyloxyphenyl)-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-4-furyl]-4-quinazolinamine;

[0146] and salts or solvates thereof, particularly pharmaceuticallyacceptable salts thereof.

[0147] Other preferred compounds of the present invention include:

[0148](4-Phenoxyphenyl)-(7-(2-(2-methanesulphonyl)ethylaminomethyl)thiazol-4-yl)-quinolin-4-yl)amine;

[0149](4-Phenoxyphenyl)-(7-(4-(2-methanesulphonyl)ethylaminomethyl)thiazol-5-yl)-quinolin-4-yl)amine;

[0150](4-Phenoxyphenyl)-(7-(5-(2-(methanesulphonyl)ethylaminomethyl)furan-2-yl)-quinolin-4-yl)amine;

[0151] and salts or solvates thereof, particularly pharmaceuticallyacceptable salts thereof.

[0152] Other preferred compounds of the present invention include thefollowing (in groups denoted hereafter as Lists 1 to 48):

[0153] List 1

[0154](4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0155](1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0156](4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0157](4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0158](4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0159](4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0160] List 2

[0161](1-Benzyl-1H-indazol-5-yl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0162](4-(4-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0163](4-(3-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0164](4-Benzenesulphonyl-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0165](4-Benzyloxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0166](4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0167]

[0168] List 3

[0169](1-Benzyl-1H-indazol-5-yl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0170](4-(4-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0171](4-(3-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0172](4-Benzenesulphonyl-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-5-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0173](4-Benzyloxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0174](4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0175] List 4

[0176](1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0177](4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0178](4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0179](4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0180](4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0181](4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0182] List 5

[0183](1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0184](4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0185](4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0186](4-Benzenesulphonyl-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0187](4-Benzyloxy-phenyl)-(6-(5-((2-methanesulphony-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0188](4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0189] List 6

[0190] (1-Benzyl-1H-indazol-5-yl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0191](4-(4-Fluorobenzyloxy)-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0192](4-(3-Fluorobenzyloxy)-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0193](4-Benzenesulphonyl-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0194](4-Phenoxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0195] List 7

[0196](1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0197](4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0198](4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0199](4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0200](4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0201](4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0202] List 8

[0203](4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;

[0204](4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;

[0205] List 9

[0206](1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;

[0207](4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;

[0208](4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;

[0209](4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine;

[0210](4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;

[0211] List 10

[0212](1-Benzyl-1H-indazol-5-yl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;

[0213](4-(4-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;

[0214](4-(3-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;

[0215](4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;

[0216] List 11

[0217](1-Benzyl-1H-indazol-5-yl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;

[0218](4-(4-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;

[0219](4-(3-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;

[0220](4-Benzenesulphonyl-phenyl)-(-2-(-methanesulphonyl-ethylamino)-methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;

[0221] (4-Benzyloxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;

[0222] (4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;

[0223] List 12

[0224](1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;

[0225](4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphony-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;

[0226](4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;

[0227](4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;

[0228](4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;

[0229](4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;

[0230] List 13

[0231](1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;

[0232](4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;

[0233](4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;

[0234](4-Benzenesulphonyl-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;

[0235](4-Benzyloxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;

[0236](4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;

[0237] List 14

[0238] (1-Benzyl-1H-indazol-5-yl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine;

[0239](4-(4-Fluorobenzyloxy)-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine;

[0240](4-(3-Fluorobenzyloxy)-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine;

[0241](4-Benzenesulphonyl-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinazolin-4-yl)-amine;

[0242](4-Benzyloxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinazolin-4-yl)-amine;

[0243](4-Phenoxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinazolin-4-yl)-amine;

[0244] List 15

[0245](1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine;

[0246](4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine;

[0247](4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine;

[0248](4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinazolin-4-yl)-amine;

[0249](4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinazolin-4-yl)-amine;

[0250](4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinazolin-4-yl)-amine;

[0251] List 16

[0252](4-(4-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphony-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;

[0253](⁴-(³-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;

[0254](4-Benzenesulphonyl-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine;

[0255](4-Benzyloxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;

[0256] (4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;

[0257] List 17

[0258](1-Benzyl-1H-indazol-5-yl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;

[0259](4-(4-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphony-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;

[0260](4-(3-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphony-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;

[0261](4-Benzenesulphonyl-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine;

[0262] (4-Benzyloxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;

[0263](4-Phenoxy-phenyl)-(7-(4-((2-methanesulphony-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;

[0264] List 18

[0265](1-Benzyl-1H-indazol-5-yl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;

[0266](4-(4-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;

[0267](4-(3-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;

[0268](4-Benzenesulphonyl-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;

[0269](4-Benzyloxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;

[0270](4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;

[0271] List 19

[0272](1-Benzyl-1H-indazol-5-yl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;

[0273](4-(4-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;

[0274](4-(3-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;

[0275](4-Benzenesulphonyl-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;

[0276](4-Benzyloxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;

[0277](4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;

[0278] List 20

[0279](1-Benzyl-1H-indazol-5-yl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;

[0280](4-(4-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;

[0281](4-(3-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;

[0282](4-Benzenesulphonyl-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;

[0283](4-Benzyloxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;

[0284](4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;

[0285] List 21

[0286](1-Benzyl-1H-indazol-5-yl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;

[0287](4-(4-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;

[0288](4-(3-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;

[0289](4-Benzenesulphonyl-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;

[0290](4-Benzyloxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;

[0291](4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-1-2-yl)-quinazolin-4-yl)-amine;

[0292] List 22

[0293](1-Benzyl-1H-indazol-5-yl)-(7-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine;

[0294](4-(4-Fluorobenzyloxy)-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine;

[0295](4-(3-Fluorobenzyloxy)-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine;

[0296](4-Benzenesulphonyl-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinazolin-4-yl)-amine;

[0297](4-Benzyloxy-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinazolin-4-yl)-amine;

[0298](4-Phenoxy-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinazolin-4-yl)-amine;

[0299] List 23

[0300](1-Benzyl-1H-indazol-5-yl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine;

[0301](4-(4-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine;

[0302](4-(3-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine;

[0303](4-Benzenesulphonyl-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinazolin-4-yl)-amine;

[0304](4-Benzyloxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinazolin-4-yl)-amine;

[0305](4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinazolin-4-yl)-amine;

[0306] List 24

[0307](1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0308](4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0309](4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0310](4-Benzenesulphonyl-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0311] (4-Benzyloxy-phenyl)-(6-(5-((2-methanesulphonyl-ethyl amino)methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0312](4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0313] List 25

[0314](1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0315](4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0316](4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0317](4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0318](4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0319](4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0320] List 26

[0321](1-Benzyl-1H-indazol-5-yl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0322](4-(4-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0323] (4-(3-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0324](4-Benzenesulphonyl-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-4-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0325](4-Benzyloxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0326](4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0327] List 27

[0328] (1-Benzyl-1H-indazol-5-yl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0329](4-(4-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0330](4-(3-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0331](4-Benzenesulphonyl-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-5-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0332](4-Benzyloxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0333](4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0334] List 28

[0335](1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0336](4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0337](4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0338](4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0339](4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0340] (4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyi-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0341] List 29

[0342](1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0343](4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-y)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0344](4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0345](4-Benzenesulphonyl-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0346] (4-Benzyloxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0347](4-Phonoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0348] List 30

[0349](1-Benzyl-1H-indazol-5-yl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0350](4-(4-Fluorobenzyloxy)-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0351](4-(3-Fluorobenzyloxy)-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0352](4-Benzenesulphonyl-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0353](4-Benzyloxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0354](4-Phenoxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0355] List 31

[0356](1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0357](4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0358](4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0359](4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0360](4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0361](4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;

[0362] List 32

[0363](4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine;

[0364](4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine;

[0365](4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinolin-4-yl)-amine;

[0366](4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinolin-4-yl)-amine;

[0367](4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;

[0368](4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;

[0369](4-Phenoxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinolin-4-yl)-amine;

[0370](4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinolin-4-yl)-amine;

[0371] List 33

[0372](1-Benzyl-1H-indazol-5-yl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine;

[0373](4-(4-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphony-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine;

[0374](4-(3-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine;

[0375] (4-Benzenesulphonyl-phenyl)-(7-(5((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinolin-4-yl)-amine;

[0376](4-Benzyloxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine;

[0377](4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine;

[0378] List 34

[0379](1-Benzyl-1H-indazol-5-yl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine;

[0380](4-(4-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesuphony-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine;

[0381](4-(3-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine;

[0382](4-Benzenesulphonyl-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinolin-4-yl)-amine;

[0383] (4-Benzyloxy-phenyl)-(7-(4-((2-methanesulphony-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine;

[0384](4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine;

[0385] List 35

[0386](1-Benzyl-1H-indazol-5-yl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinolin-4-yl)-amine;

[0387](4-(4-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinolin-4-yl)-amine;

[0388](4-(3-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinolin-4-yl)-amine;

[0389](4-Benzenesulphonyl-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-4-yl)-quinolin-4-yl)-amine;

[0390](4-Benzyloxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinolin-4-yl)-amine;

[0391](4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinolin-4-yl)-amine;

[0392] List 36

[0393](1-Benzyl-1H-indazol-5-yl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinolin-4-yl)-amine;

[0394](4-(4-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinolin-4-yl)-amine;

[0395] (4-(3-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinolin-4-yl)-amine;

[0396](4-Benzenesulphonyl-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-5-yl)-quinolin-4-yl)-amine;

[0397](4-Benzyloxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinolin-4-yl)-amine;

[0398] (4-Phen oxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinolin-4-yl)-amine;

[0399] List 37

[0400](1-Benzyl-1H-indazol-5-yl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;

[0401](4-(4-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;

[0402](4-(3-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;

[0403](4-Benzenesulphonyl-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;

[0404](4-Benzyloxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;

[0405](4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;

[0406] List 38

[0407] (1-Benzyl-1H-indazol-5-yl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;

[0408](4-(4-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;

[0409](4-(3-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;

[0410](4-Benzenesulphonyl-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;

[0411](4-Benzyloxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;

[0412](4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;

[0413] List 39

[0414](1-Benzyl-1H-indazol-5-yl)-(7-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinolin-4-yl)-amine;

[0415](4-(4-Fluorobenzyloxy)-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinolin-4-yl)-amine;

[0416](4-(3-Fluorobenzyloxy)-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinolin-4-yl)-amine;

[0417](4-Benzenesulphonyl-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinolin-4-yl)-amine;

[0418](4-Benzyloxy-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinolin-4-yl)-amine;

[0419](4-Phenoxy-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinolin-4-yl)-amine;

[0420] List 40

[0421](1-Benzyl-1H-indazol-5-yl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinolin-4-yl)-amine;

[0422](4-(4-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinolin-4-yl)-amine;

[0423](4-(3-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinolin-4-yl)-amine;

[0424](4-Benzenesulphonyl-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinolin-4-yl)-amine;

[0425](4-Benzyloxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinolin-4-yl)-amine;

[0426](4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinolin-4-yl)-amine;

[0427] List 41

[0428](4-Benzyloxy-3-chlorophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0429](4-(3-Fluoro-benzyloxy)-3-chlorophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0430](4-Benzyloxy-3-trifluoromethylphenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0431](4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0432](4-Benzyloxy-3-bromophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0433](4-(3-Fluoro-benzyloxy-3-bromophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0434](4-Benzyloxy-3-iodophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0435](4-(3-Fluoro-benzyloxy-3-iodophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0436](4-Benzyloxy-3-fluorophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0437](4-(3-Fluoro-benzyloxy-3-fluorophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0438] List 42

[0439](4-Benzyloxy-3-chlorophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0440](4-(3-Fluoro-benzyloxy)-3-chlorophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0441](4-Benzyloxy-3-trifluoromethylphenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0442](4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0443](4-Benzyloxy-3-bromophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0444](4-(3-Fluoro-benzyloxy-3-bromophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0445](4-Benzyloxy-3-iodophenyl)-(6(2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0446](4-(3-Fluoro-benzyloxy-3-iodophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0447](4-Benzyloxy-3-fluorophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0448](4-(3-Fluoro-benzyloxy-3-fluorophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0449] List 43

[0450](4-Benzyloxy-3-chlorophenyl)-(6-(2-((2-methanesulphony-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine

[0451](4-(3-Fluoro-benzyloxy)-3-chlorophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;

[0452](4-Benzyloxy-3-trifluoromethylphenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;

[0453](4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;

[0454](4-Benzyloxy-3-bromophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;

[0455](4-(3-Fluoro-benzyloxy-3-bromophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;

[0456](4-Benzyloxy-3-iodophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;

[0457](4-(3-Fluoro-benzyloxy-3-iodophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;

[0458] List 44

[0459](4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine;

[0460](4-Benzyloxy-3-bromophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine;

[0461](4-(3-Fluoro-benzyloxy-3-bromophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine;

[0462](4-Benzyloxy-3-iodophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine;

[0463](4-(3-Fluoro-benzyloxy-3-iodophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine.

[0464] List 45

[0465]N-[4-(Benzyloxy)-3-chlorophenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0466]N-[4-(3-Fluoro-benzyloxy)-3-chlorophenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0467]N-[4-Benzyloxy-3-trifluoromethylphenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0468]N-[4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0469]N-[4-Benzyloxy-3-bromophenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0470]N-[4-(3-Fluoro-benzyloxy-3-bromophenyl]-7-methoxy-6-[5-(I[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0471]N-[4-Benzyloxy-3-iodophenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0472]N-[4-(3-Fluoro-benzyloxy-3-iodophenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0473]N-[4-Benzyloxy-3-fluorophenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0474]N-[4-(3-Fluoro-benzyloxy-3-fluorophenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0475]N-[1-(3-Fluorobenzyl-1H-indazol-5-yl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0476] List 46

[0477]N-[4-(Benzyloxy)-3-chlorophenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0478]N-[4-(3-Fluoro-benzyloxy)-3-chlorophenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

[0479]N-[4-Benzyloxy-3-trifluoromethylphenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

[0480]N-[4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

[0481]N-[4-Benzyloxy-3-bromophenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

[0482]N-[4-(3-Fluoro-benzyloxy-3-bromophenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

[0483]N-[4-Benzyloxy-3-iodophenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

[0484]N-[4-(3-Fluoro-benzyloxy-3-iodophenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

[0485]N-[4-Benzyloxy-3-fluorophenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

[0486]N-[4-(3-Fluoro-benzyloxy-3-fluorophenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

[0487]N-[1-(3-fluorobenzyl-1H-indazol-5-yl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

[0488] List 47

[0489]N-[4-(benzyloxy)-3-chlorophenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0490]N-[4-(3-Fluoro-benzyloxy)-3-chlorophenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0491]N-[4-Benzyloxy-3-trifluoromethylphenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0492]N-[4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4yl]-4-quinazolinamine;

[0493]N-[4-Benzyloxy-3-bromophenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0494]N-[4-(3-Fluoro-benzyloxy-3-bromophenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0495]N-[4-Benzyloxy-3-iodophenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0496]N-[4-(3-Fluoro-benzyloxy-3-iodophenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0497]N-[4-Benzyloxy-3-fluorophenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0498]N-[4-(3-Fluoro-benzyloxy-3-fluorophenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0499]N-[1-(3-fluorobenzyl-1H-indazol-5-yl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0500] List 48

[0501]N-[4-(benzyloxy)-3-chlorophenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0502]N-[4-(3-Fluoro-benzyloxy)-3-chlorophenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0503]N-[4-Benzyloxy-3-trifluoromethylphenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0504]N-[4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0505]N-[4-Benzyloxy-3-bromophenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0506]N-[4-(3-Fluoro-benzyloxy-3-bromophenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0507]N-[4-Benzyloxy-3-iodophenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0508]N-[4-(3-Fluoro-benzyloxy-3-iodophenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0509]N-[4-Benzyloxy-3-fluorophenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;2N-[4-(3-Fluoro-benzyloxy-3-fluorophenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0510]N-[1-(3-fluorobenzyl-1H-indazol-5-yl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0511] and salts or solvates thereof, particularly pharmaceuticallyacceptable salts or solvates thereof.

[0512] Particularly preferred compounds of the present inventioninclude:

[0513](4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0514](4-Benzyloxyphenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine;

[0515]N-{4-[(3-Fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0516] N-[4-(Benzyloxy)phenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0517]N-(1-Benzyl-1H-indazol-5-yl)-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0518]N-{3-Fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0519]N-[1-(3-Fluorobenzyl)-1H-indazol-5-yl]-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0520]6-[5-({[2-(Methanesulphonyl)ethyl]amino}methyl)-2-furyl]-N-[4-(benzenesulphonyl)phenyl]-4-quinazolinamine;

[0521]N-{3-Fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0522]N-(1-Benzyl-1H-indazol-5-yl)-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[0523]N-(3-Fluoro-4-benzyloxyphenyl)-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-4-furyl]-4-quinazolinamine;

[0524]N-(3-Chloro-4-benzyloxyphenyl)-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-4-furyl]-4-quinazolinamine;

[0525]N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0526]N-(1-Benzyl-1H-indazol-5-yl)-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;

[0527]N-(3-Trifluoromethyl-4-benzyloxyphenyl)-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-4-furyl]-4-quinazolinamine;

[0528] and salts or solvates thereof, particularly pharmaceuticallyacceptable salts or solvates thereof.

[0529] Further particularly preferred compounds of the present inventioninclude:

[0530](4-Phenoxyphenyl)-(7-(2-(2-methanesulphonyl)ethylaminomethyl)thiazol-4-yl)-quinolin-4-yl)amine;

[0531](4-Phenoxyphenyl)-(7-(4-(2-methanesulphonyl)ethylaminomethyl)thiazol-5-yl)-quinolin-4-yl)amine;

[0532](4-Phenoxyphenyl)-(7-(5-(2-(methanesulphonyl)ethylaminomethyl)furan-2-yl)-quinolin-4-yl)amine;

[0533] and salts or solvates thereof, particularly pharmaceuticallyacceptable salts or solvates thereof.

[0534] Other particularly preferred compounds of the present inventioninclude:

[0535](4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;

[0536](4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;

[0537](4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;

[0538](4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;

[0539](4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;

[0540](4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;

[0541](4-Phenoxy-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine;

[0542](4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine;

[0543](4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine;

[0544](4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine;

[0545](4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinolin-4-yl)-amine;

[0546](4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinolin-4-yl)-amine;

[0547](4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;

[0548](4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;

[0549] (4-Phenoxy-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinolin-4-yl)-amine;

[0550](4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinolin-4-yl)-amine;

[0551] and salts or solvates thereof, particularly pharmaceuticallyacceptable salts or solvates thereof.

[0552] Other most particularly preferred compounds of the presentinvention include:

[0553](4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinolin-4-yl)-amine;

[0554](4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinolin-4-yl)-amine;

[0555](4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;

[0556](4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;

[0557] and salts or solvates thereof, particularly pharmaceuticallyacceptable salts or solvates thereof.

[0558] Certain compounds of formula (I) may exist in stereoisomericforms (e.g. they may contain one or more asymmetric carbon atoms or mayexhibit cis-trans isomerism). The individual stereoisomers (enantiomersand diastereoisomers) and mixtures of these are included within thescope of the present invention. Likewise, it is understood thatcompounds of formula (I) may exist in tautomeric forms other than thatshown in the formula and these are also included within the scope of thepresent invention.

[0559] Salts of the compounds of the present invention may comprise acidaddition salts derived from a nitrogen in the compound of formula (I).The therapeutic activity resides in the moiety derived from the compoundof the invention as defined herein and the identity of the othercomponent is of less importance although for therapeutic andprophylactic purposes it is, preferably, pharmaceutically acceptable tothe patient. Examples of pharmaceutically acceptable acid addition saltsinclude those derived from mineral acids, such as hydrochloric,hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, andorganic acids, such as tartaric, acetic, trifluoroacetic, citric, malic,lactic, fumaric, benzoic, glycolic, gluconic, succinic andmethanesulphonic and arylsulphonic, for example p-toluenesulphonic,acids.

[0560] According to a further aspect of the present invention there isprovided a process for the preparation of a compound of formula (I) asdefined above which comprises the steps:

[0561] (a) the reaction of a compound of formula (II)

[0562] wherein X is as defined above;

[0563] Y′ is CL′ and V′ is N;

[0564] or Y′ is N and V′ is CL′;

[0565] or Y′ is CL′ and V′ is CR²;

[0566] or Y′ is CR² and V′ is CL′;

[0567] wherein R² is as defined above, and L and L′ are suitable leavinggroups, with a compound of formula (III)

UNH₂  (III)

[0568] wherein U is as defined above, to prepare a compound of formula(IV)

[0569] and subsequently (b) reaction with appropriate reagent(s) tosubstitute the group R¹ by replacement of the leaving group L′; and, ifdesired, (c) subsequently converting the compound of formula (I) therebyobtained into another compound of formula (I) by means of appropriatereagents.

[0570] Alternatively, the compound of formula (II) as defined above isreacted with the appropriate reagents to substitute the group R¹ byreplacement of the leaving group L′ and then the product therebyobtained (of formula (V) below) is reacted with the compound of formula(III) as defined above, followed, if desired, by conversion of thecompound of formula (I) thereby obtained into another compound offormula (I).

[0571] In a variant of this alternative the compound of formula (V)

[0572] wherein X, Y, V, U and L are as defined above, may be prepared bythe reaction of a compound of formula (VI)

[0573] wherein V′ and Y′ are as defined above, with appropriate reagentsto substitute the group R¹ for the leaving group L′ to prepare acompound of formula (VII)

[0574] and subsequent reaction to incorporate the leaving group L. Forexample, a chloro leaving group can be incorporated by reaction of acorresponding 3,4-dihydropyrimidone with carbontetrachloride/triphenylphosphine in an appropriate solvent.

[0575] The group R¹ may, therefore, be substituted onto the basic ringsystem by replacement of a suitable leaving group. This may, forexample, be carried out by reaction of the corresponding aryl orheteroaryl stannane derivative with the corresponding compound offormula (IV) carrying the leaving group L′ in the appropriate positionon the ring.

[0576] According to a further aspect of the present invention there isprovided a process for the preparation of a compound of formula (I) asdefined above which comprises the steps:

[0577] (a) reacting a compound of formula (IV) as defined above withappropriate reagent(s) to prepare a compound of formula (VIII)

[0578] wherein X and U are as defined above;

[0579] Y″ is CT and V″ is N;

[0580] or Y″ is N and V″ is CT;

[0581] or Y″ is CT and V″ is CR²;

[0582] or Y″ is CR² and V″ is CT; wherein R² is as defined above and Tis an appropriately functionalised group;

[0583] and (b) subsequently converting the group T into the group R¹ bymeans of appropriate reagent(s); and, if desired, (c) subsequentlyconverting the compound of formula (I) thereby obtained into anothercompound of formula (I) by means of appropriate reagents.

[0584] In one alternative, the group T would represent a group Ar asdefined above carrying a formyl group (CHO).

[0585] Where T represents a group Ar carrying a formyl group thecompound (of formula (VIIIa)) may be suitably prepared from thecorresponding dioxolanyl substituted compound (of formula (VIIIb)), forexample by acid hydrolysis. The dioxolanyl substituted compound may beprepared by reaction of a compound of formula (IV) with an appropriatereagent to substitute the relevant leaving group with the substituentcarrying the dioxolanyl ring. This reagent could, for example, be anappropriate heteroaryl stannane derivative.

[0586] Therefore a suitable process may comprise reaction of a compoundof formula (VIIIa) in which T is a group Ar carrying a formylsubstituent (i.e. a —CHO group) with a compound of formulaCH₃SO₂CH₂CH₂NH₂. The reaction preferably involves a reductive aminationby means of an appropriate reducing agent, for example sodiumtriacetoxyborohydride.

[0587] Alternatively, another suitable process may comprise oxidation ofa compound of formula (VIIIc) in which T is a group Ar carrying asubstituent of formula CH₃SCH₂CH₂NHCH₂ or CH₃SOCH₂CH₂NHCH₂. Suitablemethods for the oxidation to the desired compound of formula (I) will bewell known to the person skilled in the art but include, for example,reaction with an organic peroxide, such as peracetic acid ormetachlorobenzoic acid, or reaction with an inorganic oxidising agent,such as OXONE®. The compound of formula (VIIIc) in which T is a group Arcarrying a substituent of formula CH₃SCH₂CH₂NHCH₂ or CH₃SOCH₂CH₂NHCH₂may be prepared by an analogous reaction to that described above, namelyreaction of a compound of formula (VIIIa) in which T is a group Arcarrying a formyl substituent (i.e. a —CHO group) with a compound offormula CH₃SCH₂CH₂NH₂ or CH₃SOCH₂CH₂NH₂ respectively.

[0588] Alternatively, an analogous scheme to those described above couldbe used wherein the substitution of the group R¹ onto the basic ringsystem occurs prior to the coupling reaction with the compound offormula (III).

[0589] According to a further alternative process the group T isconverted into the group R¹ by a de novo synthesis of a substitutedheterocyclic system using appropriate agents. Such a process wouldinvolve standard synthetic methodology known to the person skilled inthe art for building up the heterocylic ring system.

[0590] For example, T could represent a haloketone group as shown in thecompound of formula (IX) in scheme 1 below which, when coupled with anappropriate N-protected thioamide [compound of formula (XI) in scheme2], would result in the formation of an N-protected amino-substitutedthiazole system of formula (X).

[0591] Scheme 1 outlines, for example, the synthesis of derivativescarrying a substituted thiazole ring as an R¹ substituent:

[0592] wherein halo is as previously defined (preferably iodo), and P′in the compound of formula (XI) is a suitable protecting group, such astrifluorocarbonyl.

[0593] An analogous process may be used to prepare compounds offormula(I) which carry R¹ in the 7-position of the basic ring systemfrom a starting compound of formula(IVb)

[0594] via intermediates of formulae (Xb) and (XIb) which arerespectively analogous to those of formulae (Xa) and (XIb).

[0595] An appropriately substituted thioamide coupling reagent, suitablefor preparation of a thiazole ring system, may be prepared according toScheme 2:

[0596] Wherein in scheme 2 the trifluorocarbonyl protecting group in thecompounds of formula (XIV), (XV) and (XVIa) is equivalent to the groupP′ in scheme 1.

[0597] Alternatively, an analogous scheme to those described above couldbe used wherein the substitution of the group R¹ onto the basic ringsystem occurs prior to the coupling reaction with the compound offormula(III).

[0598] Other substituted thioamides are prepared using analogousprocesses to that shown above.

[0599] In general, the group R² will be present as a substituent in thebasic ring system prior to the introduction of the group R¹ or the groupNHU. Where R² is other than hydrogen it may in certain circumstances benecessary to protect the group prior to performing the reaction steps tointroduce the R¹ and NHU substituents. Particular mention should be madeof the situation where R² is hydroxy; suitable protecting groups toensure non-interference with the subsequent reaction steps include the2-to methoxyethoxymethyl ether (MEM) group or a bulky silyl protectinggroup such as tert-butyldiphenylsilyl (TBDPS).

[0600] Suitable protecting groups, methods for their introduction andmethods for their removal would be well known to the person skilled inthe art. For a description of protecting groups and their use see T. W.Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, 2ndedn., John Wiley & Sons, New York, 1991.

[0601] Suitable leaving groups for L and L′ will be well known to thoseskilled in the art and include, for example, halo such as fluoro,chloro, bromo and iodo; sulphonyloxy groups such as methanesulphonyloxyand toluene-p-sulphonyloxy; alkoxy groups; and triflate.

[0602] The coupling reaction referred to above with the compound offormula (III) is conveniently carried out in the presence of a suitableinert solvent, for example a C₁₋₄ alkanol, such as isopropanol, ahalogenated hydrocarbon, an ether, an aromatic hydrocarbon or a dipolaraprotic solvent such as acetone, acetonitrile or DMSO at a non-extremetemperature, for example from 0 to 150° C., suitably 10 to 120° C.,preferably 50 to 100° C.

[0603] Optionally, the reaction is carried out in the presence of abase. Examples of suitable bases include an organic amine such astriethylamine, or an alkaline earth metal carbonate, hydride orhydroxide, such as sodium or potassium carbonate, hydride or hydroxide.

[0604] The compound of formula (I) may be obtained from this process inthe form of a salt with the acid HL, wherein L is as hereinbeforedefined, or as the free base by treating the salt with a base ashereinbefore defined.

[0605] The compounds of formulae (II) and (III) as defined above, thereagents to substitute the group R¹, and the reagent(s) to convert thegroup T into the group R¹ are either readily available or can be readilysynthesised by those skilled in the art using conventional methods oforganic synthesis.

[0606] As indicated above, the compound of formula (I) prepared may beconverted to another compound of formula (I) by chemical transformationof the appropriate substituent or substituents using appropriatechemical methods (see for example, J.March “Advanced Organic Chemistry”,Edition III, Wiley Interscience, 1985).

[0607] For example, a compound containing an alkylthio group may beoxidised to the corresponding sulphinyl or sulphonyl compound by use ofan organic peroxide (e.g. benzoyl peroxide) or suitable inorganicoxidant (eg OXONE®).

[0608] A compound containing a nitro substituent may be reduced to thecorresponding amino-compound, e.g. by use of hydrogen and an appropriatecatalyst (if there are no other susceptible groups), by use of RaneyNickel and hydrazine hydrate or by use of iron/acetic acid.

[0609] Amino substituents may be acylated by use of an acid chloride oran anhydride under appropriate conditions. Equally an amide group may becleaved to the amino compound by treatment with, for example, diluteaqueous base.

[0610] An amino substituent may also be converted to a dimethylaminosubstituent by reaction with formic acid and sodium cyanoborohydride.Similarly, reaction of a primary or secondary amino group with anothersuitable aldehyde under reducing conditions will lead to thecorresponding substituted amine.

[0611] All of the above-mentioned chemical transformations may also beused to convert any relevant intermediate compound to anotherintermediate compound prior to the final reaction to prepare a compoundof formula (I); this would thus include their use to convert onecompound of formula (III) to a further compound of formula (III) priorto any subsequent reaction.

[0612] Various intermediate compounds used in the above-mentionedprocesses, including but not limited to certain of the compounds offormulae (II), (III), (IV), (V), (VI), (VII) and (VIII) as illustratedabove, are novel and thus represent a further aspect of the presentinvention.

[0613] In particular, a further aspect of the present invention isintermediate compounds of formulae (VIIIa) and (VIIIb) defined above,with the exception of the following compounds:

[0614](1-Benzyl-1H-indazol-5-yl)-(6-(5-[1,3-dioxolan-2-yl]-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0615]5-(4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde;

[0616]5-(4-(4-Benzyloxy-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaidehyde;

[0617](4-Benzyloxy-phenyl)-(6-(5-[1,3-dioxolan-2-yl]-furan-2-yl)-quinazolin-4-yl)-amine;

[0618]5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde;

[0619](1-Benzyl-1H-indazol-5-yl)-(6-(5-[1,3-dioxolan-2-yl]-furan-2-yl)-quinazolin-4-yl)-amine;

[0620]5-(4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-6-yl)-furan-2-carbaldehyde;

[0621]5-(4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-6-yl)-1-methyl-pyrrole-2-carbaldehyde;

[0622](1-Benzyl-1H-indazol-5-yl)-(7-(5-[1,3-dioxolan-2-yl]-furan-2-yl)-quinazolin-4-yl)-amine;

[0623]5-(4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-7-yl)-furan-2-carbaldehyde.

[0624] In particular, a yet further aspect of the present invention isintermediate compounds of formula (VIIIc) as defined above;

[0625] with the proviso that the following compound is excluded:

[0626](4-Benzyloxy-phenyl)-(6-(5-((2-methanesulphinyl-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine.

[0627] In particular, another further aspect of the present invention isintermediate compounds of formulae (X), (XI), (XII), (XIII), (XIV), (XV)and (XVI) as defined above.

[0628] The compounds of formula (I) and salts thereof have anticanceractivity as demonstrated hereinafter by their inhibition of the proteintyrosine kinase c-erbB-2, c-erbB-4 and/or EGF-R enzymes and their effecton selected cell lines whose growth is dependent on c-erbB-2 or EGF-rtyrosine kinase activity. Certain compounds of formula (I) are alsodemonstrated hereinafter to inhibit Ick and/or zap70 protein tyrosinekinase enzymes and are expected to have activity in disease conditionsin which T cells are hyperactive.

[0629] The present invention thus also provides compounds of formula (I)and pharmaceutically acceptable salts or solvates thereof for use inmedical therapy, and particularly in the treatment of disorders mediatedby aberrant protein tyrosine kinase activity such as human malignanciesand the other disorders mentioned above. The compounds of the presentinvention are especially useful for the treatment of disorders caused byaberrant c-erbB-2 and/or EGF-r and/or Ick activity such as breast,ovarian, gastric, pancreatic, non-small cell lung, bladder, head andneck cancers, psoriasis and rheumatoid arthritis.

[0630] A further aspect of the invention provides a method of treatmentof a human or animal subject suffering from a disorder mediated byaberrant protein tyrosine kinase activity, including susceptiblemalignancies, which comprises administering to said subject an effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt or solvate thereof.

[0631] A further aspect of the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, in therapy.

[0632] A further aspect of the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, in the preparation of a medicament for the treatment ofcancer and malignant tumours.

[0633] A further aspect of the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, in the preparation of a medicament for the treatment ofpsoriasis.

[0634] A further aspect of the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, in the preparation of a medicament for the treatment ofrheumatoid arthritis

[0635] Whilst it is possible for the compounds, salts or solvates of thepresent invention to be administered as the new chemical, it ispreferred to present them in the form of a pharmaceutical formulation.

[0636] According to a further feature of the present invention there isprovided a pharmaceutical formulation comprising at least one compoundof formula (I), or a pharmaceutically acceptable salt or solvatethereof, together with one or more pharmaceutically acceptable carriers,diluents or excipients.

[0637] Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain for example 0.5 mg to 1 g, preferably 70 mg to700 mg, more preferably 5 mg to 100 mg of a compound of the formula (I)depending on the condition being treated, the route of administrationand the age, weight and condition of the patient.

[0638] Pharmaceutical formulations may be adapted for administration byany appropriate route, for example by the oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) route. Such formulations maybe prepared by any method known in the art of pharmacy, for example bybringing into association the active ingredient with the carrier(s) orexcipient(s).

[0639] Pharmaceutical formulations adapted for oral administration maybe presented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

[0640] Pharmaceutical formulations adapted for transdermaladministration may be presented as discrete patches intended to remainin intimate contact with the epidermis of the recipient for a prolongedperiod of time. For example, the active ingredient may be delivered fromthe patch by iontophoresis as generally described in PharmaceuticalResearch, 3(6), 318 (1986).

[0641] Pharmaceutical formulations adapted for topical administrationmay be formulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

[0642] For treatments of the eye or other external tissues, for examplemouth and skin, the formulations are preferably applied as a topicalointment or cream. When formulated in an ointment, the active ingredientmay be employed with either a paraffinic or a water-miscible ointmentbase. Alternatively, the active ingredient may be formulated in a creamwith an oil-in-water cream base or a water-in-oil base.

[0643] Pharmaceutical formulations adapted for topical administrationsto the eye include eye drops wherein the active ingredient is dissolvedor suspended in a suitable carrier, especially an aqueous solvent.

[0644] Pharmaceutical formulations adapted for topical administration inthe mouth include lozenges, pastilles and mouth washes.

[0645] Pharmaceutical formulations adapted for rectal administration maybe presented as suppositories or as enemas.

[0646] Pharmaceutical formulations adapted for nasal administrationwherein the carrier is a solid include a coarse powder having a particlesize for example in the range 20 to 500 microns which is administered inthe manner in which snuff is taken, i.e. by rapid inhalation through thenasal passage from a container of the powder held close up to the nose.Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or as nasal drops, include aqueous oroil solutions of the active ingredient.

[0647] Pharmaceutical formulations adapted for administration byinhalation include fine particle dusts or mists which may be generatedby means of various types of metered dose pressurised aerosols,nebulizers or insufflators.

[0648] Pharmaceutical formulations adapted for vaginal administrationmay be presented as pessaries, tampons, creams, gels, pastes, foams orspray formulations.

[0649] Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets.

[0650] Preferred unit dosage formulations are those containing a dailydose or sub-dose, as herein above recited, or an appropriate fractionthereof, of an active ingredient.

[0651] It should be understood that in addition to the ingredientsparticularly mentioned above, the formulations may include other agentsconventional in the art having regard to the type of formulation inquestion, for example those suitable for oral administration may includeflavouring agents.

[0652] The animal requiring treatment with a compound, salt or solvateof the present invention is usually a mammal, such as a human being.

[0653] A therapeutically effective amount of a compound, salt or solvateof the present invention will depend upon a number of factors including,for example, the age and weight of the animal, the precise conditionrequiring treatment and its severity, the nature of the formulation, andthe route of administration, and will ultimately be at the discretion ofthe attendant physician or veterinarian However, an effective amount ofa compound of the present invention for the treatment of neoplasticgrowth, for example colon or breast carcinoma, will generally be in therange of 0.1 to 100 mg/kg body weight of recipient (mammal) per day andmore usually in the range of 1 to 10 mg/kg body weight per day. Thus,for a 70 kg adult mammal, the actual amount per day would usually befrom 70 to 700 mg and this amount may be given in a single dose per dayor more usually in a number (such as two, three, four, five or six) ofsub-doses per day such that the total daily dose is the same. Aneffective amount of a salt or solvate of the present invention may bedetermined as a proportion of the effective amount of the compound perse. It is envisaged that similar dosages would be appropriate fortreatment of the other conditions referred to above.

[0654] The compounds of the present invention and their salts andsolvates may be employed alone or in combination with other therapeuticagents for the treatment of the above-mentioned conditions. Inparticular, in anti-cancer therapy, combination with otherchemotherapeutic, hormonal or antibody agents is envisaged. Combinationtherapies according to the present invention thus comprise theadministration of at least one compound of formula (I) or apharmaceutically acceptable salt or solvate thereof and at least oneother pharmaceutically active agent. The compound(s) of formula (I) andthe other pharmaceutically active agent(s) may be administered togetheror separately and, when administered separately this may occursimultaneously or sequentially in any order. The amounts of thecompound(s) of formula (I) and the other pharmaceutically activeagent(s) and the relative timings of administration will be selected inorder to achieve the desired combined therapeutic effect.

[0655] Certain embodiments of the present invention will now beillustrated by way of example only. The physical data given for thecompounds exemplified is consistent with the assigned structure of thosecompounds.

[0656]¹H NMR spectra were obtained at 500 MHz on a Bruker AMX500spectrophotometer, on a Bruker spectrophotometer at 300 MHz, on a BrukerAC250 or Bruker AM250 spectrophotometer at 250 MHz and on a Varian UnityPlus NMR spectrophotometer at 300 or 400 MHz. J values are given in Hz.Mass spectra were obtained on one of the following machines: VGMicromass Platform (electrospray positive or negative), HP5989A Engine(thermospray positive) or Finnigan-MAT LCQ (ion trap) mass spectrometer.Analytical thin layer chromatography (tic) was used to verify the purityof some intermediates which could not be isolated or which were toounstable for full characterisation, and to follow the progess ofreactions. Unless otherwise stated, this was done using silica gel(Merck Silica Gel 60 F254). Unless otherwise stated, columnchromatography for the purification of some compounds used Merck Silicagel 60 (Art. 1.09385, 230-400 mesh), and the stated solvent system underpressure.

[0657] Petrol refers to petroleum ether, either the fraction boiling at40-60° C., or at 60-80° C.

[0658] Ether refers to diethylether.

[0659] DMSO refers to dimethylsulphoxide.

[0660] THF refers to tetrahydrofuran.

[0661] HPLC refers to high pressure liquid chromatography.

[0662] NMM refers to N-methylmorpholine

[0663] Useful preparative techniques are described in WO96/09294,WO97103069, WO97/13771, WO95/19774, WO96/40142 and WO97/30034; alsodescribed in these publications are appropriate intermediate compoundsother than those detailed below.

[0664] Preparation processes specified in the prior art or in theexperimental details below for compounds with a particular basic ringsystem (1) to (6) above may be suitably adapted for others of thesebasic ring systems.

[0665] General Procedures

[0666] (A) Reaction of an Amine with a Bicyclic Species Containing a4-chloropyrimidine or 4-chloropyridine Ring

[0667] The optionally substituted bicyclic species and the specifiedamine were mixed in an appropriate solvent (typically acetonitrileunless otherwise specified, although ethanol, 2-propanol or DMSO mayalso be used), and heated to reflux. When the reaction was complete (asjudged by tic), the reaction mixture was allowed to cool. The resultingsuspension was diluted, e.g. with acetone, and the solid collected byfiltration, washing e.g. with excess acetone, and dried at 60° C. invacuo, giving the product as the hydrochloride salt. If the free basewas required (e.g. for further reaction), this was obtained by treatmentwith a base e.g. triethylamine; purification by chromatography was thenperformed if required.

[0668] (B) Reaction of a Product from Procedure (A) with a HeteroarylTin Reagent

[0669] A stirred mixture of the product from Procedure (A), (containinga suitable leaving group such as chloro, bromo, iodo or triflate), aheteroaryl stannane and a suitable palladium catalyst, such asbis(triphenylphosphine)palladium (II) chloride or1,4-bis(diphenylphosphino)butane palladium (II) chloride (prepared asdescribed in C.E. Housecroft et. al., Inorg. Chem., (1991), 30(1),125-130), together with other appropriate additives (such asdiisopropylethylamine or lithium chloride), were heated at reflux in drydioxane or another suitable solvent (e.g. DMF) under nitrogen until thereaction was complete. The resulting mixture was generally purified bychromatography on silica.

[0670] (C) Removal of a 1,3-dioxolan-2-yl Protecting Group to Liberatean Aldehyde

[0671] The compound containing the 1,3-dioxolan-2-yl group was suspendedin an appropriate solvent, e.g.THF and treated with hydrochloric acid,either as an aqueous solution (e.g. 2N) or as a solution in dioxane(e.g. 4 molar) and stirred at ambient temperature until the reaction wasjudged complete (e.g. by tic or LC/MS analysis). Generally the mixturewas diluted with water, and the resulting precipitate was collected byfiltration, washed with water and dried to give the aldehyde.

[0672] (D) Reaction of an Aldehyde with an Amine by Reductive Amination

[0673] An aldehyde (such as the product of General Procedure C) and therequired primary or secondary amine were stirred together in a suitablesolvent (such as dichloromethane) containing glacial acetic acid (4Amolecular sieves may also be present) for ca. 1 h. A suitable reducingagent, such as sodium (triacetoxy) borohydride was then added andstirring continued under nitrogen until the reaction was complete (asjudged by hplc or tic). The resulting mixture was washed with an aqueousbasic solution (e.g. sodium or potassium carbonate) and extracted with asuitable solvent, e.g. dichloromethane. The dried organic phase wasevaporated and the residue purified either by column chromatography orby Bond Elut™ cartridge. If desired, the isolated material was thenconverted into the hydrochloride salt e.g. by treatment with etherealhydrogen chloride.

[0674] (E) Reaction sequence to Prepare Appropriately SubstitutedThioamides

[0675] E-1 Reaction of an Aminosulfide with Chloroacetonitrile

[0676] To a stirred mixture of an aminosulfide and a suitable base suchas sodium bicarbonate or sodium carbonate in an appropriate solvent(typically acetonitrile, although DMF or dioxane can be used) was addedchloroacetonitrile dropwise. The resulting mixture was heated to refluxuntil the reaction was complete. The solid was filtered and the filtratewas concentrated to provide the corresponding aminonitrile.

[0677] E-2 Trifluoroacetamide Protection of an Aminonitrile

[0678] A solution of the aminonitrile (such as the product of generalprocedure A) and an amine base, such as triethylamine or NMM in asuitable solvent (e.g. dichloromethane), was cooled to 0° C. andtrifluoroacetic anhydride was added Fe dropwise. The resulting mixturewas stirred at room temperature until the reaction was complete. Waterwas added and the mixture was extracted with a suitable solvent (e.g.dichloromethane), the organic layer was dried over anhydrous magnesiumsulfate and concentrated. The crude product was purified by columnchromatography to provide the corresponding trifluoroacetamide.

[0679] E-3 Oxidation of a Cyanosulfide

[0680] To a stirred solution of a sulfide (such as the product ofgeneral procedure E1) in a suitable solvent (typically methanol/water(2:1), although dichloromethane can be used) cooled to 0° C. was addedan oxidizing agent (typically oxone, although MCPBA can be used). Theresulting mixture was stirred at room temperature until the reaction wascomplete. The reaction was concentrated to remove any organic solvents,diluted with water, and extracted with an appropriate solvent (e.g.dichloromethane). The organic layer was dried and concentrated toprovide the corresponding cyanosulfone.

[0681] E-4 Preparation of Thioamides

[0682] To a solution of a cyanosulfone (such as the product of generalprocedure E-3) and an organic base (e.g. triethylamine) in THF was addedhydrogen sulfide gas. The resulting mixture was stirred at roomtemperature until the reaction was complete. The mixture wasconcentrated and triturated with hexane to provide thioamide.

[0683] (F) Reaction sequence to Prepare an Optionally SubstitutedThiazole

[0684] F-1 Reaction of a Vinylstannane with a Product from Procedure (A)

[0685] A stirred mixture of the optionally substituted bicyclic4-anilinopyrimidine species, tributyl(1-ethoxyvinyl)stannane (1 to 5molar equivalents), and a suitable palladium catalyst (0.03 to 0.1 molarequivalents), such as bis(triphenylphosphine) palladium (II) chloride ortetrakis(triphenylphosphine) palladium (O) was heated at reflux in anappropriate solvent (typically acetonitrile, although DMF or dioxane canbe used) until the reaction was complete. The resulting mixture wasconcentrated and generally purified by trituration with diethyl ether toprovide the corresponding bicyclic pyrimidine vinyl ether.

[0686] F-2 Reaction of a Product from Procedure (F-1) with a BrominationReagent

[0687] A bicyclic pyrimidine vinyl ether (such as the product of generalprocedure F-1) and 1 equivalent of a bromination reagent, such asN-bromosuccinimide or bromine, were stirred at 0° C. in a suitablesolvent (typically 10% aqueous THF or dichloromethane) until thereaction was complete. The resulting mixture was dried over anhydrousmagnesium sulfate and concentrated, or in the case of bromine the solidwas filtered, to provide the corresponding (α-bromoketone.

[0688] F-3 Reaction of a Product from Procedure (F-2) with a Productfrom Procedure (E-4)

[0689] A stirred mixture of an (α-bromoketone (such as the product ofgeneral procedure F-2) and thioamide from Procedure E-4 in a 1:1 molarratio was heated to 70-100° C. in an appropriate solvent (typically DMF,although acetonitrile and THF can be used) until the reaction wascomplete. The resulting mixture was washed with an aqueous basicsolution (e.g. sodium carbonate) and extracted with a suitable solvent,e.g. ethyl acetate. The dried organic layer was concentrated and theresidue was purified by column chromatography to provide thecorresponding trifluoroacetamide aminothiazole.

[0690] F-4 Removal of a Trifluoroacetamide Protecting Group to Liberatean Aminothiazole

[0691] A mixture of a trifluoroacetamide protected aminothiazole (suchas the product of general procedure F-3) in 2M NaOH/methanol (1:1) wasstirred at room temperature until the reaction was complete. The mixturewas concentrated, poured into water and extracted with an appropriatesolvent e.g. 10% MeOH/dichloromethane. The dried organic layer wasconcentrated, then dissolved in ethyl acetate/MeOH (1:1) and treatedwith 4M HCl/dioxane. The resulting solid was filtered to provide thecorresponding amine hydrochloride salt.

[0692] Synthesis of Intermediates

[0693] N-5-[N-tert-Butoxncarbonyl)amino]-2-chloropyridine

[0694] A stirred solution of 6-chloronicotinic acid (47.3 g),diphenylphosphoryl azide (89.6 g) and triethylamine (46 ml) in t-butanol(240 ml) were heated under reflux under nitrogen for 2.5 hours. Thesolution was cooled and concentrated in vacuo. The syrupy residue waspoured into 3 liters of a rapidly stirred solution of 0.33N aqueoussodium carbonate. The precipitate was stirred for one hour and filtered.The solid was washed with water and dried in vacuo at 70° C. to give thetitle compound (62 g) as a pale brown solid; m.p. 144-146° C.; δH[²H₆]-DMSO 8.25(1H, d), 7.95 (1H, bd), 7.25 (1H, d), 6.65(1H, bs), 1.51(9H, s); m/z (M+1)⁺229.

[0695] This material may subsequently be carried forward to theappropriately substituted pyridopyrimidine intermediate according to theprocedures as described in WO95/19774, J. Med. Chem., 1996, 39, pp1823-1835, and J. Chem. Soc., Perkin Trans. 1,1996, pp 2221-2226.Specific compounds made by such procedures include6-chloro-pyrido[3,4-d]pyrimidin-4-one and4,6-dichloro-pyrido[3,4-d]pyrimidine.

[0696] 2-Amino-4-fluoro-5-iodo-benzoic Acid

[0697] To a vigorously stirred solution of dichloromethane (700 ml),methanol (320 ml), and 2-amino-4-fluoro-benzoic acid (33.35 grams, 215mmoles) was added solid sodium hydrogencarbonate (110 grams, 1.31 moles)followed by portion addition of benzyltrimethyl ammonium dichloroiodate(82.5 grams, 237 mmoles). The mixture was allowed to stir for 48 hours.The mixture was filtered to remove the insolubles. The remaining solidresidue was washed with 200 ml of dichloromethane. The filtrate wasconcentrated and redissolved in a one to one mixture of ethyl acetate (1liter) and a 0.2 N solution of sodium hydroxide (1 liter), added to a 2liter separatory funnel and extracted. The organic layer was washed withan additional 200 ml of water. The aqueous layers were combined andacidified with 2N hydrochloric acid. The resulting precipitate wascollected by suction filtration, washed with water and dried undervacuum at 60° C. to yield 46.5 grams (77%) of the title compound. ¹H NMR(400 MHz, DMSO-d₆) δ: 8.04(d, 1H), 7.1(s, broad, 2H), 6.63(d, 1H).ESI-MS m/z 280 (M−1).

[0698] 4-Fluoro-5-iodo-isatoic Anhydride

[0699] Anhydrous dioxane (0.5 liters), 2-amino-4-fluoro-5-iodo-benzoicacid (46 grams, 164 mmoles), and trichloromethylchloroformate (97.4grams, 492 mmoles) were added to a one liter one neck flask equippedwith a magnetic stir bar and reflux condenser. The solution was placedunder anhydrous nitrogen, stirred and heated to reflux for 16 hours. Thereaction mixture was allowed to cool and was poured into one liter ofhexanes. The solid was collected by suction filtration, washed with anadditional 0.5 liters of hexanes, and dried under vacuum at roomtemperature to yield 45.5 grams (90%) of the title compound ¹H NMR (400MHz, DMSO-d₆) δ: 11.86(s, 1H), 8.24(d, 1H), 6.84(d, 1H). ESI-MS m/z 308(M+1).

[0700] 4-Chloro-6-bromoquinazoline and 4-Chloro-6-iodoquinazoline werePrepared as Described in WO 96/09294.

[0701] 4-Hydroxy-6-iodo-7-fluoroquinazoline

[0702] Dimethylformamide (0.5 liters), 4-fluoro-5-iodo-isatoic anhydride(45 grams, 147 mmoles), and formamidine acetate (45.92 grams, 441mmoles), were combined in a one liter one-neck flask fitted with amagnetic stir bar. The mixture was placed under anhydrous nitrogen andheated at 110° C. for 6 hours. The mixture was allowed to cool, followedby concentrating the reaction mixture to one third its original volumeon the rotary evaporator. The resulting mixture was poured onto 3 litersof ice water. The resulting precipitated solid was collected by suctionfiltration. The solid was washed with an additional one liter ofdistilled water. The resulting solid was dried under vacuum at 70° C. toyield 38.9 grams (91%) of the title compound. ¹H NMR (400 MHz, DMSO-d₆)δ: 12.43(s, 1H), 8.46(d, 1H), 8.12(s, 1H), 7.49(d, 1H). ESI-MS m/z291(M+1).

[0703] 4-Chloro-6-iodo-7-fluoro-quinazoline Hydrochloride

[0704] Thionyl chloride (0.6 liters),4-hydroxy-6-iodo-7-fluoro-quinazoline (36 grams, 124 mmoles), anddimethylformamide (6 ml) were combined in a one liter one-neck flaskfitted with a magnetic stir bar. The mixture was placed under anhydrousnitrogen and heated to a gentle reflux for 24 hours. The mixture wasallowed to cool, followed by concentrating the reaction mixture to athick yellowish residue. To this residue was added dichloromethane (0.1liter) and toluene (0.1 liter). The mixture was concentrated to dryness.This procedure was repeated two additional times. To the resulting solidwas added 0.5 liters of dry dichloromethane and the mixture was stirredfor one hour. The mixture was filtered and the remaining solids werewashed with minimal dichloromethane. The dichoromethane filtrates werecombined, concentrated to a solid, and dried under vacuum at roomtemperature to yield 28.6 grams (67%) of the title compound. ¹H NMR (400MHz, CDCl₃-d₁) δ: 9.03(s, 1H), 8.76(d, 1H), 7.69(d, 1H). ESI-MS m/z309(M+1).

[0705] 2-Bromo-4-(1,3-dioxolan-2-yl) Thiazole

[0706] 2-Bromothiazole-4-carbaldehyde (6.56 g, 34.17 mmol) [A.T. Ung,S.G.Pyne/Tetrahedron: Asymmetry 9 (1998) 1395-1407]and ethylene glycol(5.72 ml, 102.5 mmol) were heated under reflux in toluene (50 ml),with aDean and Stark trap fitted, for 18hr. The product was concentrated andpurified by column chromatography (15% ethyl acetate/hexane) to give theproduct as a yellow solid (6.03 g); m/z 236,238.

[0707] 4-(1,3-Dioxolan-2-yl)-5-(tributylstannyl)thiazole

[0708] 2-Bromo-4-(1,3-dioxolan-2-yl) thiazole (6.4 g, 27.14 mmol) wasstirred at −78° C. in dry THF (38 ml). 1.6M n butyl lithium in hexane(18.6 ml, 29.78 mmol) was added dropwise under nitrogen. After 30 min atthis temperature, tributyl tin chloride (7.35 ml, 27.14 mmol) was addeddropwise. The reaction was allowed to warm to 0° and water (20 ml) wasadded. The product was extracted into ether (3×100 ml). The combinedorganic extracts were dried (MgSO₄) and evaporated. The residue wastriturated with isohexane (3×1 00 ml) and the mother liquors weredecanted, combined and concentrated to give a brown oil (11.88 g); m/z444-450.

[0709] 1-N-Benzyl-5-nitro-1H-indazole and 2-N-Benzyl-5-nitro-1H-indazole

[0710] A stirred mixture of 5-nitroindazole (50 g), potassium carbonate(46.6 g, 1.1 equiv.) and benzyl bromide (57.6 g, 1.1 equiv) inN,N-dimethylformamide (500 ml) was heated at 75° C. for a period of 4hours. The reaction was then cooled and water (500 ml) was graduallyadded to precipitate the product which was filtered off and washed withwater (50 ml) and dried in the air at ambient temperature. The weight ofpale yellow solid thus obtained was 72.3 g (93%), m.p. 95-97° C.; HPLC(Partisil 5, dichloromethane, 4 ml/min, 250 nm) gave an isomer ratio(1-N-benzyl: 2-N-benzyl) of 63:37 (RT-1 N 3.4 min, RT-2N 6.6 min). To afiltered solution of the mixed regioisomers (100 g) in acetone (470 ml)at room temperature was added, gradually with stirring, water (156 ml)and the mixture was stirred for one hour. The resultant yellowcrystalline solid was filtered off and dried in the air at ambienttemperature to give 36.4 g (34%) of material; m.p.124-126° C.; HPLCshowed an isomer ratio (1-N-benzyl: 2-N-benzyl) of 96:4; δH (CDCl₃) 5.58(2H, s, CH₂), 7.12-7.15(2H) & 7.22-7.29(3H)-(phenyl), 7.33 (1H, dt, J=1Hz & 9 Hz, H-7), 8.15(1H, dd, J=2 Hz & 9 Hz, H-6), 8.19(1H, d, J=1 Hz,H-3), 8.67 (1H, dd, J=1 Hz & 2 Hz, H-4).

[0711] Also note the published method in FR 5600, Jan. 8, 1968.

[0712] 5-Amino-1-N-benzyl-1H-indazole

[0713] 1-Benzyl-5-nitroindazole (400 g) was suspended in ethanol (5liter) and hydrogenated in the presence of 5% platinum on carboncatalyst (20 g) operating at 1 bar pressure and 50-60° C. When hydrogenuptake was complete the reactor contents were heated to 70° C.,discharged and filtered while still hot and the filtrate concentrated to˜4 liter which caused some crystallisation. Water (4 liter) was thengradually added with stirring and the mixture was stirred at 5° C.overnight. The resultant crystals were filtered off and air-dried atambient temperature to give 305 g (86%) of material, m.p.150-152° C.;HPLC (Supelcosil ABZ+, gradient 0.05% trifluoroacetic acid inwater/0.05% trifluoroacetic acid in acetonitrile, 1.5 ml/min, 220 nm)showed<1% of the corresponding 2-N-isomer (RT-1N 6.03 min, RT-2N 5.29min); δH (CDCl₃) 3.3-3.8(2H, broad s, NH₂), 5.47 (2H, s, CH₂), 6.74 (1H,dd, J=2 Hz & 9 Hz, H-6), 6.87 (1H, dd, J=1 Hz & 2 Hz, H-4),7.06-7.11(3H) & 7.17-7.25 (3H)-(phenyl & H-7), 7.77 (1H, d, J=1 Hz,H-3).

[0714] Also note the published method in FR 5600,Jan. 8, 1968.

[0715] 1-Benzyl-3-methyl-5-nitro-1H-indazole

[0716] 2-Fluoro-5-nitroacetophenone (H. Sato et al, Bioorganic andMedicinal Chemistry Letters, 5(3), 233-236,1995) (0.24 g) was treatedwith triethylamine (0.73 ml)and benzyl hydrazine dihydrochloride (0.255g) in ethanol (20 ml) at reflux under N₂ for 8 days. The mixture wascooled and the solid 1-benzyl-3-methyl-5-nitroindazole (0.16 g) wascollected by filtration; m/z (M+1)⁺268.

[0717] 1-Benzyl-3-methyl-1H-indazol-5-ylamine

[0718] 1-Benzyl-3-methyl-5-nitroindazole (0.15 g) in THF (15 ml) wastreated with platinum on carbon (0.05 g, 5%) under an atmosphere ofhydrogen at room temperature. When hydrogen uptake was complete, themixture was filtered and concentrated in vacuo to give the titlecompound; m/z (M+1)⁺268.

[0719] Further Amino-indazole Intermediates

[0720] The relevant nitro-substituted 1H-indazole was treated with abase such as potassium carbonate or sodium hydroxide in a suitablesolvent, such as acetone or acetonitrile. The appropriate aryl halide orheteroaryl halide was added and the reaction mixture heated or stirredat room temperature overnight. Subsequent concentration in vacuo andchromatography on silica gave the desired 1-substitutednitro-1H-indazoles. Hydrogenation was carried out by analogy with thepreparation of 5-amino-1-benzyl-1H-indole described above.

[0721] Amines prepared by such methods include:

[0722] 5-Amino-1-benzyl-1H-indazole; m/z (M+1)⁺224

[0723] 5-Amino-1-(2-fluorobenzyl)-1H-indazole; m/z (M+1)⁺242

[0724] 5-Amino-1-(3-fluorobenzyl)-1H-indazole; m/z (M+1)⁺242

[0725] 5-Amino-1-(4-fluorobenzyl)-1H-indazole; m/z (M+1)⁺242

[0726] 5-Amino-1-(2-pyridylmethyl)-1H-indazole; m/z (M+1)⁺225

[0727] 5-Amino-1-(3-pyridylmethyl)-1H-indazole; m/z (M+1)⁺225

[0728] 5-Amino-1-(4-pyridylmethyl)-1H-indazole; m/z (M+1)⁺225

[0729] 5-Amino-1-(2,3-difluorobenzyl)-1H-indazole; m/z (M+1)⁺260

[0730] 5-Amino-1-(3,5-difluorobenzyl)-1H-indazole; m/z (M+1)⁺260.

[0731] 1-Benzenesulphonylindol-5-yl-amine was prepared according to thepublished method (J. Org. Chem., 55,1379-90, (1990)).

[0732] 4-Benzyloxyaniline is commercially available as the hydrochloridesalt; this is treated with aqueous sodium carbonate solution, and themixture extracted with ethyl acetate; the organic solution is dried(MgSO₄) and concentrated to give the free base as a brown solid, usedwithout further purification.

[0733] Other substituted anilines were in general prepared by analogousmethods to those outlined in WO 96/09294 and/or as follows:

[0734] Step 1:

[0735] Preparation of the Precursor Nitro-Compounds

[0736] 4-Nitrophenol (or an appropriate substituted analogue, such as3-chloro-4-nitrophenol) was treated with a base such as potassiumcarbonate or sodium hydroxide in an appropriate solvent, such as acetoneor acetonitrile. The appropriate aryl or heteroaryl halide was added andthe reaction mixture heated or stirred at room temperature overnight.

[0737] Purification A:

[0738] Most of the acetonitrile was removed in vacuo, and the residuewas partitioned between water and dichloromethane. The aqueous layer wasextracted with further dichloromethane (×2), and the combineddichloromethane layers were concentrated in vacuo.

[0739] Purification B: Removal of insoluble material by filtration,followed by concentration of the reaction mixture in vacuo, andchromatography on silica.

[0740] Step 2:

[0741] Reduction to the Corresponding Aniline

[0742] The precursor nitro compound was reduced by catalytichydrogenation at atmospheric pressure using 5% Pt/carbon, in a suitablesolvent (eg ethanol, THF, or mixtures thereof to promote solubility).When reduction was complete, the mixture was filtered throughHarborlite™, washing with excess solvent, and the resulting solutionconcentrated in vacuo to give the desired aniline. In some cases, theanilines were acidified with HCl (e.g. in a solution in dioxane) to givethe corresponding hydrochloride salt.

[0743] Anilines prepared by such methods include:

[0744] 4-(2-Fluorobenzyloxy)aniline; m/z (M+1)⁺218

[0745] 4-(3-Fluorobenzyloxy)aniline; m/z (M+1)⁺218

[0746] 4-(4-Fluorobenzyloxy)aniline; m/z (M+1)⁺218

[0747] 3-Chloro-4-(2-fluorobenzyloxy)aniline; m/z (M+1)⁺252

[0748] 3-Chloro-4-(3-fluorobenzyloxy)aniline; m/z (M+1)⁺252

[0749] 3-Chloro-4-(4-fluorobenzyloxy)aniline; m/z (M+1)⁺252

[0750] 4-Benzyloxy-3-chloroaniline; m/z (M+1)⁺234

[0751] and, in appropriate cases, their hydrochloride salts.

[0752] 4-Benzenesulphonylaniline was prepared by the published method(Helv. Chim. Acta., 1983, 66(4), p1046.

[0753] 4-Benzyloxy-3-trifluoromethyl-nitrobenzene

[0754] 60% NaH dispersion (1.4 g, 33.5 mmol) in mineral oil was washedwith hexanes and then suspended in DMF (10 ml). To this NaH suspensionin DMF, added benzyl alcohol (2.8 ml, 26.3 mmol) with water bath to keepthe temperature below 30 ° C. The reaction mixture was stirred until theevolution of the hydrogen gas ceased. To a solution of2-fluoro-5-nitrobenzotrifluoride (5.0 g, 23.9 mmol) in DMF (20 ml) wasadded the benzyl alkoxide solution slowly at 0 ° C. Upon the completionof the addition, the ice bath was removed and the reaction mixture wasstirred at room temperature for 2 hours. The reaction mixture was pouredinto 200 ml ice water, stirred until the yellow solid was formed.Filtered and the solid was washed with water and then trituated withpentane. 5.9 g yellow solid was collected (yield: 83%). ESI-MS m/z 298(M+H)⁺

[0755] 4-Benzyloxy-3-trifluoromethyl-aniline

[0756] Raney Ni suspension (about 200 mg Ni) was stirred with methanol.The supernate was decanted. This was repeated twice and then freshmethanol was added. To this suspension of Ni in methanol, was added2-O-benzyl-5-nitrotrifluoride (375 mg, 1.26 mmol). With the water bathto keep the temperature below 30° C., the hydrazine hydrate (189 mg,3.79 mmol) was slowly added. Upon the completion of addition, thereaction mixture was stirred at room temperature for 10 minutes and then45° C. until evolution of nitrogen gas ceased. Filtered through Celite®and the filtrate was concentrated under reduced pressure. 336 mg thickyellow syrup was obtained (yield: 100%). ESI-MS m/z 268 (M+H)⁺.

[0757] 4-(Tributylstannyl)thiazole-2-carbaldehyde

[0758] 4-Bromo-2-(tributylstannyl)thiazole (T. R. Kelly and F. Lang,Tetrahedron Lett., 36, 9293, (1995)) (15.0 g) was dissolved in THF (150ml) under a nitrogen atmosphere, cooled to −85° C. and treated witht-BuLi (1.7M, in pentane, 43 ml). The mixture was stirred at −85° C. for30 min, and then N-formylmorpholine (8.4 g) was added by syringe. Afterfurther stirring at −85° C. for 10 min the mixture was allowed to warmto room temperature. Water (200 ml) was added and the mixture wasextracted with diethyl ether (4×100 ml). The combined ethereal extractswere washed with water, dried (NaSO₄), and concentrated in vacuo.Chromatography on silica, eluting with 10%ether/hexane, gave the titlecompound as a yellow oil; δH [²H₆]DMSO 10.03 (1H, s), 8.29 (1H, s),1.55(6H, q), 1.21-1.37 (6H, m), 1.09-1.20 (6H, m), 0.85 (9H, t).

[0759](1-Benzyl-1H-indazol-5-yl)-(6-chloropyrido[3,4-d]pyrimidin-4-yl)-amineHydrochloride

[0760] Prepared according to Procedure A from1-benzyl-1H-indazol-5-ylamine and 4,6-dichloropyrido[3,4-d]pyrimidine;δH [²H₆]-DMSO 9.08 (1H, s), 8.92 (1H, s), 8.82 (1H, s), 8.23 (1H, d),8.19 (1H, s), 7.80 (1H, d), 7.70 (1H, dd), 7.38-7.22 (5H, m), 5.69 (2H,s); m/z (M+1)⁺387.

[0761](1-Benzyl-1H-indazol-5-yl)-(6-(5-[1,3-dioxolan-2-yl]-furan-2-yl)-pyrido[3.4-d]-pyrimidin-4-yl)-amine

[0762](1-Benzyl-1H-indazol-5-yl)-(6-chloropyrido[3,4-d]pyrimidin-4-yl)-amine(4.28 g), 2-(tributylstannyl)-5-(1,3-dioxolan-2-yl)-furan (J. Chem Soc.,Chem. Commun., (1988), p560) (10 g) and 1,4-bis(diphenylphosphino)butanepalladium (II) chloride (1 g) were heated at reflux in dioxane (150 ml)for 24 hr (Procedure B). The solvent was removed in vacuo and theresidue chromatographed on silica. Subsequent trituration gave the titlecompound as a yellow solid; δH [²H₆]-DMSO 10.46 (1H, s), 9.17 (1H, s),8.74 (1H, s), 8.52 (1H, s), 8.23 (1H, s), 8.18 (1H, s), 7.80-7.68 (2H,m), 7.41-7.22 (5H, m), 7.17 (1H, d), 6.80 (1H, d), 6.06 (1H, s), 5.71(2H, s), 4.20-3.96 (4H, m).

[0763]5-(4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde

[0764](1-Benzyl-1H-indazol-5-yl)-(6-(5-[1,3-dioxolanyl]-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine(3.03 g) and 2N HCl (50 ml) were stirred in THF (50 ml) for 16 hr. Theresulting precipitate was filtered and washed with water to give thehydrochloride salt of the product; δH [²H₆]DMSO 11.70 (1H, s), 9.74 (1H,s) 9.30 (1H, s), 9.27 (1H, s), 8.85 (1H, s), 8.23 (1H, s), 8.18 (1H, s),7.68-7.87 (3H, m), 7.55 (1H, d), 7.22-7.38 (5H, m), 5.71 (2H, s).Subsequent neutralisation with triethylamine in ethanol/water gave thetitle compound; δH [²H₆]-DMSO 9.64(1H, s), 9.19 (1H, s), 9.09(1H, s),8.72(1H, s), 8.12(2H, m), 7.71 (2H, m), 7.63(1H, dd), 7.43(1H, d),7.20(5H, m), 5.62(2H, s).

[0765] (4-Benzyloxyphenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine

[0766] Prepared according to Procedure A from 4-benzyloxyaniline and4,6-dichloro-pyrido[3,4-d]yrimidine; δH (CDCl₃) 9.11 (1H, s), 8.78 (1H,s), 7.75 (1H, d), 7.56 (2H, dd), 7.40 (5H, m), 7.15 (2H, d), 5.10 (2H,s); m/z (M+1)⁺409.

[0767]5-(4-(4-Benzyloxy-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde

[0768] (4-Benzyloxyphenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine(4.0 g, 11.0 mmol), 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan (J.Chem. Soc., Chem. Commun., (1988), 560) (6.0 g, 14.0 mmol) were reactedtogether in a procedure analogous to Procedure B above for 20hrs. Thereaction mixture was allowed to cool, 1 N HCl (50 ml) added and stirredat room temperature for 15 minutes. The reaction was filtered and theresidue washed with dioxane (20 ml) and 2N HCl (20 ml). The combinedfiltrate and washings were stirred at room temperature for a furtherhour. The dioxane was removed under vacuum, the reaction diluted withwater and the solid which precipitated was collected by filtration, andwashed with water, iso-hexane and acetone. This precipitate wasconverted to the free base by partitioning into a mixture oftriethylamine, ethyl acetate and water. The organic phase was washedwith water, dried (magnesium sulphate) and the solvent removed undervacuum. The residue was triturated with iso-hexane/ethyl acetate to givethe product (2.41 g, 52%) as a yellow solid; δH [²H₆]-DMSO 10.60 (1H, b,NH), 9.83 (1H, s, CHO), 9.30 (1H, s, 2-H), 9.08 (1H, s, 5-H or 8-H),8.76 (1H, s, 5-H or 8-H), 7.89 (1H, d, furan-H), 7.82 (2H, d, 2′-H,6′-H), 7.65-7.42 (6H, m, 5×Ph-H, furan-H), 7.21 (2H, d, 3′-H, 5′-H),5.26 (2H, s, OCH₂); m/z (M+1)⁺423.

[0769](4-Benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine

[0770] Reaction of(4-benzyloxyphenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)amine (5.44 g,15.0 mmol), 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan (10.4 g, 24.2mmol) and bis(triphenylphosphine)palladium (II) chloride (catalyticamount) in dioxane (150 ml) according to Procedure B, followed bypurification by silica gel chromatography (eluted with 50-100%EtOAc/i-hexane), allowed the isolation of the dioxolane product (3.45 g,7.40 mmol, 49%); δH [²H₆]DMSO 10.28 (1H, s), 9.13 (1H, s), 8.69 (1H, s),8.61 (1H, s), 7.71 (2H, d), 7.31-7.52 (5H, m), 7.14 (1H, d), 7.09 (2H,d), 6.77 (1H, d), 6.03 (1H, s), 5.15 (2H, s), 3.95-4.19 (4H, m). Thiscould then be converted to5-(4-(4-Benzyloxy-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde(identical to that described above) using Procedure C.

[0771] (4-Phenoxyphenyl)-(7-iodoquinolin-4-yl)amine

[0772] 4-Chloro-7-iodoquinoline (10 g, 34 mmol) [Semenov, V. P.;Studenikov, A. N. Synthesis of 7-iodo-4-aminoquinoline derivatives.Khim. Geterotsikl. Soedin. (1980), Issue 7, 972-5] and 4-phenoxyaniline(6.38 g, 34 mmol) in butanol (75 ml) were heated at gentle reflux (120°C.) overnight (18 hrs). On cooling the resultant precipitate wascollected by filtration and washed with acetonitrile (2×50 ml). Theresultant solid was suspended in chloroform (500 ml) and 2N sodiumcarbonate solution (300 ml) and heated at 75° C. for 45 mins. On coolingthe resultant precipitate was collected by filtration, washed with water(2×50 ml) and dried to yield the product as a pale brown solid. (9.95 g,66%) δH [²H₆]DMSO 8.35(3H, m), 8.20(1H, s), 8.10(1H, d), 7.85(1H, s),7.35(4H, m), 7.15(4H, d), 6.75(1H, d).

[0773] (4-Benzyloxyphenyl)-(6-bromoquinazolin-4-yl)-amine Hydrochloride

[0774] 4-Chloro-6-bromoquinazoline (0.25 g, 1.0 mmol) and4-benzyloxyaniline (0.25 g, 1.3 mmol) were mixed in 2-propanol (6 ml)and heated at reflux for 10 mins (Procedure A). The solution was allowedto cool at room temperature and the 2-propanol removed in vacuo. Theresulting solid was triturated with acetone to give the product as ayellow solid (0.39 g, 88%); δH [²H₆]-DMSO 11.60 (1H, b, NH), 9.21 (1H,s, 5-H), 8.86 (1H, s, 2-H), 8.20 (1H, d, 7-H), 7.90 (1H, d, 8-H), 7.65(2H, d, 2′-H, 6′-H), 7.50-7.25 (5H, m, Ph-H), 7.10 (2H, d, 3′-H, 5′-H),5.15 (2H, s, CH₂); m/z 405/407 (M+).

[0775] (4-Benzyloxyphenyl)-(6-iodoquinazolin-4-yl)-amine Hydrochloride

[0776] 4-Chloro-6-iodoquinazoline (8 g) was treated with4-benzyloxyaniline (5.5 g) in acetonitrile (500 ml) at reflux under N₂for 18 hours. Subsequent cooling and filtration gave the title compound(13.13 g); δH [²H₆]-DMSO 11.45 (1H, b, NH), 9.22 (1H, s, 5-H), 8.89 (1H,s, 2-H), 8.36 (1H, d, 7-H), 7.69 (1H, d, 8-H), 7.63 (2H, d, 2′-H, 6′-H),7.52-7.29 (5H, m, Ph-H), 7.14 (2H, d, 3′-H, 5′-H), 5.18 (2H, s, CH₂);m/Z (M+1)⁺454.

[0777] (4-Benzyloxyphenyl)-(6-iodo-7-fluoro-quinazolin-4-yl)-amineHydrochloride

[0778] Prepared according to Procedure A from4-chloro-6-iodo-7-fluoro-quinazoline hydrochloride (4.02 grams, 11.65mmoles), anhydrous dioxane (70 ml), dichloromethane (20 ml) and4-benzyloxyaniline hydrochloride (2.83 grams, 12 mmoles). The mixturewas stirred and heated to 110° C. (oil bath temperature) for 16 hours.The mixture was cooled to room temperature and filtered to remove theprecipitated solids. The solids were washed with cold anhydrous dioxane(100 ml) followed by cold anhydrous diethyl ether. The yellowish solidwas collected and dried under vacuum at room temperature to yield 4.68grams (79%) of the title compound. δH (400 MHz, DMSO-d₆): 11.2(s, 1H),9.3(d, 1H), 8.79(s, 1H), 7.64(d, 1H), 7.58(d, 2H), 7.44(d, 2H), 7.38(m,2H), 7.31 (m, 1H), 7.09(d, 2H), 5.14(s, 2H) ESI-MS m/z 472(M+1).

[0779](1-Benzyl-1H-indazol-5-yl)-(6-iodo-7-fluoro-quinazolin-4-yl)-amineHydrochloride

[0780] Prepared according to Procedure A from1-benzyl-1H-indazol-5-ylamine and 4-chloro-6-iodo-7-fluoroquinazoline.δH (400 MHz, DMSO-d₆): 11.55(s, 1H), 9.41 (d, 1H), 8.8(s, 1H), 8.18(s,1H), 8.05(d, 1H), 7.78(d, 1H), 7.69(d, 1H), 7.61 (m, 1H), 7.29(m, 2H),7.23(m, 3H), 5.67(s, 2H). ESI-MS m/z 496(M+1).

[0781](4-Benzenesulphonyl)phenyl-(6-iodo-7-fluoro-quinazolin-4-yl)-amineHydrochloride

[0782] Prepared according to Procedure A from4-(benzenesulphonyl)phenylamine and 4-chloro-6-iodo-7-fluoroquinazoline.¹H NMR (400 MHz, DMSO-d₆) δ: 10.89(s, 1H), 9.3(d, 1H), 8.79(s, 1H),8.07(d, 2H), 8.0(d, 2H), 7.94(d, 2H), 7.67(m, 2H), 7.61 (m, 2H). ESI-MSm/z 504(M−1).

[0783]6-lodo-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-quinazolin-4yl)amine

[0784] Prepared according to Procedure A from(4-(3-fluorobenzyloxy)-3-chlorophenyl)amine and4-chloro-6-iodo-quinazoline. ¹H NMR (DMSO-d6) 9.83 (s, 1H); 8.92 (s,1H); 8.58 (s, 1H); 8.09 (d, 1H); 8.00 (d, 1H); 7.61 (d, 1H); 7.52 (d,1H); 7.44 (m, 1H); 7.20-7.33 (m, 3H); 7.15 (m, 1H); 5.21 (s, 2H); MS m/z506 (M+1).

[0785]6-lodo-(4-(3-fluorobenzyloxy)-3-fluorophenyl)-quinazolin-4yl)amine

[0786] Prepared according to Procedure A from(4-(3-fluorobenzyloxy)-3-fluorophenyl)amine and4-chloro-6-iodo-quinazoline. ¹H NMR (DMSO-d6) 9.83 (s, 1H); 8.92 (s,1H); 8.57 (s, 1H); 8.08 (d, 1H); 7.85 (d, 1H); 7.53 (d, 1H); 7.50 (d,1H); 7.43 (m, 1H); 7.30-7.20 (m, 3H); 7.15 (m, 1H); 5.20 (s, 2H); MS m/z490 (M+1).

[0787]6-lodo-(4-(3-fluorobenzyloxy)-3-methoxyphenyl)-quinazolin-4yl)amine

[0788] Prepared according to Procedure A from(4-(3-fluorobenzyloxy)-3-methoxyphenyl)amine and4-chloro-6-iodo-quinazoline. ¹H NMR 400 MHz (DMSO-d6) 11.29 (bs, 1 HO;9.14 (s, 1H); 8.87 (s, 1H); 8.32 (d, 1H); 7.62 (d, 1H); 7.42 (m, 1H);7.34 (d, 1H); 7.29-7.22 (m, 3H); 7.18-7.08 (m, 2H); 5.15 (s, 2H); 3.80(s, 3H); MS m/z 502 (M+1)

[0789] 6-lodo-(4-benzyloxy-3-fluorophenyl)-quinazolin-4-yl)amine

[0790] Prepared according to Procedure A from4-benzyloxy)-3-fluorophenylamine and 4-chloro-6-iodo-quinazoline. ¹H NMR(DMSO-d6) 9.82 (s, 1H); 8.93 (s, 1H); 8.57 (s, 1H); 8.09 (d, 1H); 7.84(d, 1H); 7.51 (m, 2H); 7.44 (d, 2H); 7.37 (m, 2H); 7.33 (m, 1H); 7.24(m, 1H); 5.18 (s, 2H); MS m/z 472 (M+1)

[0791] 6-lodo-(4-(3-bromobenzyloxy)-phenyl)-quinazolin-4-yl)amine

[0792] Prepared according to Procedure A from(4-(3-bromobenzyloxy)-phenyl)amine and 4-chloro-6-iodo-quinazoline. ¹HNMR (DMSO-d6) 9.84 (s, 1H); 8.98 (s, 1H); 8.57 (s, 1H); 8.13 (m, 2H);7.71 (d, 2H); 7.56 (d, 2H); 7.50 (m, 1H); 7.41 (m, 1H); 7.08 (d, 2H);5.17 (s, 2H).

[0793] 6-lodo-(4-(3-fluorobenzyloxy)-phenyl)-quinazolin-4-yl)amine

[0794] Prepared according to Procedure A from(4-(3-fluorobenzyloxy)-phenyl)amine and 4-chloro-6-iodo-quinazoline. ¹HNMR (DMSO-d6) 9.77 (s, 1H); 8.92 (s, 1H); 8.50 (s, 1H); 8.06 (d, 1H);7.66 (d, 2H); 7.50 (d, 1H); 7.42 (m, 1H); 7.30-7.25 (m, 2H); 7.14 (m,1H); 7.03 (d, 2H); 5.13 (s, 2H); MS m/z 472 (M+1)

[0795]6-lodo-(4-(3-trifluoromethylbenzyloxy)-phenyl)-quinazolin-4-yl)amine

[0796] Prepared according to Procedure A from(4-(3-trifluoromethylbenzyloxy)-phenyl)amine and4-chloro-6-iodo-quinazoline. ¹H NMR (DMSO-d6) 9.2 (bs, 1H); 8.91 (s,1H); 8.37 (d, 1H); 7.89-7.72 (m, 8H); 7.19 (d, 2H); 5.30 (s, 2H).

[0797]6-lodo-(4-benzyloxy-3-trifluoromethyl-phenyl)-quinazolin-4-yl)amine

[0798] The mixture of 4-chloro-6-iodo-quinazoline (366 mg, 1.26 mmol)and 4-O-benzyl-3-trifluoroaniline (405 mg, 1.26 mmol) in isopropanol (12ml) was heated to reflux for 3.5 hours. Filtered, washed withisopropanol and dried. 535 mg yellow solid was afforded. (yield: 76%).ESI-MS m/z 522 (M+H)⁺.

[0799](4-Benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-fluoro-quinazolin-4-yl)-amine

[0800] Synthesized according to Procedure B from a solution of(4-benzyloxyphenyl)-(6-iodo-7-fluoro-quinazolin-4-yl)-aminehydrochloride (508 mg, 1 mmole),5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan (645 mg, 1.5 mmole),diisopropylethyl amine (650 mg, 5 mmole), anddichlorobis(triphenylphosphine) palladium (140 mg, 0.2 mmole) in 6 ml ofDMF under nitrogen was stirred at 100° C. (oil bath temperature) for 4hours. The cooled reaction mixture was extracted with water (100 ml) andethyl acetate (100 ml). The organic phase was washed with brine (100ml). The aqueous layers were combined and washed with additional ethylacetate (100 ml). The organic layers were combined, dried with MgSO₄,filtered and concentrated to a residue. The residue was chromatographedon silica gel with a methanol-chloroform mixture. Fractions werecollected, combined, and concentrated. The resultant solid was suspendedin dichloromethane (10 ml) and diethyl ether was added facilitateprecipitation. The solid was filtered and dried under vacuum at roomtemperature to yield a yellowish solid 287 mg (59%). ¹H NMR (400 MHz,DMSO-d₆) δ: 10.1(s, 1H), 8.85(d, 1H), 8.45(s, 1H), 7.6(m, 3H), 7.44(d,2H), 7.38(m, 2H), 7.31 (m, 1H), 7.03(m, 2H), 6.94(m, 1H), 6.74(d, 1H),6.01 (s, 1H), 5.1(s, 2H), 4.10(m, 2H), 3.96(m, 2H). ESI-MS m/z 482(M−1).

[0801](1-Benzyl-1H-indazol-5-yl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-fluoro-quinazolin-4-yl)-amine

[0802] Prepared according to Procedure B from(1-benzyl-1H-indazol-5-yl)-(6-iodo-7-fluoro-quinazolin-4-yl)-aminehydrochloride and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan. 67 ¹HNMR (400 MHz, DMSO-d₆) δ 10.27(s, 1H), 8.89(d, 1H), 8.46(s, 1H), 8.1 (d,2H), 7.69(d, 1H), 7.61 (m, 2H), 7.26(m, 5H), 6.96(m, 1H), 6.74(d, 1H),6.01 (s, 1H), 5.65(s, 2H), 4.09(m, 2H), 3.96(m, 2H). ESI-MS m/z506(M−1).

[0803](4-Benzenesulphonyl)phenyl-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-fluoro-quinazolin-4-yl)-amine

[0804] Prepared according to Procedure B from(4-benzenesulphonyl)phenyl-(6-iodo-7-fluoro-quinazolin-4-yl)-aminehydrochloride and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan. δ¹HNMR (400 MHz, DMSO-d₆) 10.49(s, 1H), 8.88(d, 1H), 8.63(s, 1H), 8.1(d,2H), 7.95(m, 4H), 7.65(m, 4H), 6.97(m, 1H), 6.75(d, 1H), 6.01(s, 1H),4.09(m, 2H), 3.97(m, 2H). ESI-MS m/z 516(M−1).

[0805](4-Benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazolin-4-yl)-amine

[0806] Prepared according to Procedure B from(4-benzyloxy-phenyl)-(6-bromoquinazolin-4-yl)-amine (1.5 g, 3.7 mmol)and 5-(1,3-dioxolan-2-yl)-2(tributylstannyl)-furan (1.9 g, 4.42 mmol)dissolved in dioxan (30 ml) and heated at reflux under nitrogen for 6hr. The solvent was removed from the cooled reaction under vacuum, andthe residual oil was triturated with iso-hexane/ethyl acetate to givethe product (1.07 g, 62%) as a pale yellow solid; δH [²H₆]-DMSO 9.96(1H, b, NH), 8.80 (1H, s, 5-H), 8.51 (1H, s, 2-H), 8.18 (1H, d, 7-H),7.80 (1H, d, 8-H), 7.70 (2H, d, 2′-H, 6′-H), 7.58-7.30 (5H, m, 5 ×Ph-H),7.10 (3H, m, 3′-H, 5′-H, furan 3-H), 6.78 (1H, d, furan 4-H), 6.12 (1H,s, CHO₂), 5.18 (2H, s, PhCH₂), 4.22-3.94 (4H, m, 2×CH₂); m/z 466 (M+1)⁺.

[0807](4-Benzyloxy-3-trifluoromethylphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazolin-4-yl)-amine

[0808] Prepared according to Procedure B using6-lodo-(4-benzyloxy-3-trifluoromethyl-phenyl)-quinazolin-4-yl)amine (480mg, 0.92 mmol), and 5-tributyltin-(1,3-dioxolan-2-yl)-furan (731 mg,1.38 mmol) in dioxane (10 ml). The resulting product was a yellow solid(0.47 g, 95.8% yield). ESI-MS m/z 534 (M+H)⁺.

[0809]5-(4-(4-Benzyloxy-3-trifluoromethylphenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde

[0810] Prepared according to Procedure C using(4-Benzyloxy-3-trifluoromethylphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazolin-4-yl)-amine(470 mg, 0.88 mmol) solution in THF (5 ml) followed by the addition of2N HCl (20 ml) at room temperature. The resulting mixture was stirredfor 30 minutes. Water was added (15 ml) then filtered. The yellow solidwas washed with water and small amount of ether and dried in vacuo (0.39g, 84% yield). ESI-MS m/z 490 (M+H)⁺.

[0811](4-Benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-methoxy-quinazolin-4-yl)-amine

[0812] Prepared according to Procedure B from a solution of(4-benzyloxyphenyl)-7-methoxy-6-trifluoromethanesulphonyl-quinazolin-4-yl)-amine(0.30 g, 0.59 mmol), 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan(0.37 g, 0.86 mmol), lithium chloride (78 mg, 1.8 mmol), anddichloro-bis(triphenylphosphine)palladium (90 mg, 0.13 mmol) in 2 ml ofDMF under nitrogen was stirred at 85-90° C. for 50 minutes. The cooledreaction mixture was partitioned between 30 ml of water and 40 ml ofethyl acetate. The organic solution was washed with 30 ml of brine,dried with Na₂SO₄ and concentrated in vacuo. The residue waschromatographed on silica gel with hexanes/ethyl acetate (1:1 to 0:1).The resulting solution was concentrated to near dryness and theresulting solid suspended in ether and filtered to give 0.232 g ofproduct as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ: 9.90(s,1H), 8.71 (s, 1H), 8.40(s, 1H), 7.60(d, 2H), 7.44(d, 2H), 7.37(t, 2H),7.30(t, 1H), 7.24(s, 1H), 7.00(m, 3H), 6.67(d, 1H), 5.99(s, 1H), 5.09(s,2H), 4.10(m, 2H), 4.02(s, 3H), 3.95(m, 2H). ESI-MS m/z 496(M+1).

[0813](4-Benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-fluoro-quinazolin-4-yl)-amine

[0814] Prepared according to Procedure B from a solution of(4-benzyloxyphenyl)-(6-iodo-7-fluoro-quinazolin-4-yl)-aminehydrochloride (508 mg, 1 mmole),5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan (645 mg, 1.5 mmole),diisopropylethyl amine (650 mg, 5 mmole), anddichlorobis(triphenylphosphine) palladium (140 mg, 0.2 mmole) in 6 ml ofDMF under nitrogen was stirred at 100° C. (oil bath temperature) for 4hours. The cooled reaction mixture was extracted with water (100 ml) andethyl acetate (100 ml). The organic phase was washed with brine (100ml). The aqueous layers were combined and washed with additional ethylacetate (100 ml). The organic layers were combined, dried with MgSO₄,filtered and concentrated to a residue. The residue was chromatographedon silica gel with a methanol-chloroform mixture. Fractions werecollected, combined, and concentrated. The resultant solid was suspendedin dichloromethane (10 ml) and diethyl ether was added to facilitateprecipitation. The solid was filtered and dried under vacuum at roomtemperature to yield a yellow solid 287 mg (59%). ¹H NMR (400 MHz,DMSO-d₆) δ: 10.1 (s, 1H), 8.85 (d, 1H), 8.45 (s, 1H), 7.6 (m, 3H), 7.44(d, 2H), 7.38 (m, 2H), 7.31 (m, 1H), 7.03 (m, 2H), 6.94 (m, 1H), 6.74(d, 1H), 6.01 (s, 1H), 5.1 (s, 2H), 4.10 (m, 2H), 3.96 (m, 2H). ESI-MSm/z 482(M−1).

[0815] (4-Benzyloxyphenyl)-(6-iodo-7-fluoro-quinazolin-4-yl)-aminehydrochloride

[0816] Prepared according to Procedure A from4-chloro-6-iodo-7-fluoro-quinazoline hydrochloride (4.02 grams, 11.65mmoles), anhydrous dioxane (70 ml), dichloromethane (20 ml), and4-benzyloxyaniline hydrochloride (2.83 grams, 12 mmoles). The mixturewas stirred and heated to 110° C. (oil bath temperature) for 16 hours,cooled to room temperature and filtered to remove the precipitatedsolids. The solids were washed with cold anhydrous dioxane (100 ml)followed by cold anhydrous diethyl ether. The yellowish solid wascollected and dried under vacuum at room temperature to yield 4.68 grams(79%) of the title compound. δH NMR (400 MHz, DMSO-d₆): 11.2(s, 1H),9.3(d, 1H), 8.79(s, 1H), 7.64(d, 1H), 7.58(d, 2H), 7.44(d, 2H), 7.38(m,2H), 7.31 (m, 1H), 7.09(d, 2H), 5.14(s, 2H) ESI-MS m/z 472(M+1).

[0817](1-Benzyl-1H-indazol-5-yl)-(6-iodo-7-fluoro-quinazolin-4-yl)-amineHydrochloride

[0818] Prepared according to Procedure A from1-benzyl-1H-indazol-5-ylamine and 4-chloro-6-iodo-7-fluoroquinazoline.δH NMR (400 MHz, DMSO-d₆): 11.55(s, 1H), 9.41 (d, 1H), 8.8(s, 1H),8.18(s, 1H), 8.05(d, 1H), 7.78(d, 1H), 7.69(d, 1H), 7.61 (m, 1H),7.29(m, 2H), 7.23(m, 3H), 5.67(s, 2H). ESI-MS m/z 496(M+1).

[0819](4-Benzenesulphonyl)phenyl-(6-iodo-7-fluoro-quinazolin-4-yl)-amineHydrochloride

[0820] Prepared according to Procedure A from4-benzenesulphonyl)phenylamine and 4-chloro-6-iodo-7-fluoroquinazoline.8HNMR (400 MHz, DMSO-d₆) δ: 10.89(s, 1H), 9.3(d, 1H), 8.79(s, 1H),8.07(d, 2H), 8.0(d, 2H), 7.94(d, 2H), 7.67(m, 2H), 7.61(m, 2H). ESI-MSm/z 504(M−1).

[0821]6-lodo-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-quinazolin-4yl)amine

[0822] Prepared according to Procedure A from4-(3-fluorobenzyloxy)-3-chlorophenyl)-amine and4-chloro-6-iodoquinazoline. ¹H NMR (DMSO-d6) 9.83 (s, 1H); 8.92 (s, 1H);8.58 (s, 1H); 8.09 (d, 1H); 8.00 (d, 1H); 7.61 (d, 1H); 7.52 (d, 1H);7.44 (m, 1H); 7.20-7.33 (m, 3H); 7.15 (m, 1H); 5.21 (s, 2H); MS m/z 506(M+1)

[0823]6-lodo-(4-(3-fluorobenzyloxy)-3-fluorophenyl)-quinazolin-4yl)amine

[0824] Prepared according to Procedure A from(4-(3-fluorobenzyloxy)-3-fluorophenyl)-amine and4-chloro-6-iodoquinazoline. ¹H NMR (DMSO-d6) 9.83 (s, 1H); 8.92 (s, 1H);8.57 (s, 1H); 8.08 (d, 1H); 7.85 (d, 1H); 7.53 (d, 1H); 7.50 (d, 1H);7.43 (m, 1H); 7.30-7.20 (m, 3H); 7.15 (m, 1H); 5.20 (s, 2H); MS m/z 490(M+1)

[0825]6-lodo-(4-(3-fluorobenzyloxy)-3-methoxyphenyl)-quinazolin-4yl)amine

[0826] Prepared according to Procedure A from(4-(3-fluorobenzyloxy)-3-fluorophenyl)-amine and4-chloro-6-iodoquinazoline. ¹H NMR 400 MHz (DMSO-d6) 11.29 (bs, 11H0;9.14 (s, 1H); 8.87 (s, 1H); 8.32 (d, 1H); 7.62 (d, 1H); 7.42 (m, 1H);7.34 (d, 1H); 7.29-7.22 (m, 3H); 7.18-7.08 (m, 2H); 5.15 (s, 2H); 3.80(s, 3H); MS m/z 502 (M+1)

[0827] 6-lodo-(4-benzyloxy-3-fluorophenyl)-quinazolin-4-yl)amine

[0828] Prepared according to Procedure A from(4-benzyloxy-3-fluorophenyl)-amine and 4-chloro-6-iodoquinazoline. ¹HNMR (DMSO-d6) 9.82 (s, 1H); 8.93 (s, 1H); 8.57 (s, 1H); 8.09 (d, 1H);7.84 (d, 1H); 7.51 (m, 2H); 7.44 (d, 2H); 7.37 (m, 2H); 7.33 (m, 1H);7.24 (m, 1H); 5.18 (s, 2H), MS m/z 472 (M+1)

[0829] 6-lodo-(4-(3-bromobenzyloxy)-phenyl)-quinazolin-4-yl)amine

[0830] Prepared according to Procedure A from(4-(3-bromobenzyloxy)-phenyl)-amine and 4-chloro-6-iodoquinazoline. ¹HNMR (DMSO-d6) 9.84 (s, 1H); 8.98 (s, 1H); 8.57 (s, 1H); 8.13 (m, 2H);7.71 (d, 2H); 7.56 (d, 2H); 7.50 (m, 1H); 7.41 (m, 1H); 7.08 (d, 2H);5.17 (s, 2H).

[0831] 6-lodo-(4-(3-fluorobenzyloxy)-phenyl)-quinazolin-4-yl)amine

[0832] Prepared according to Procedure A from(4-(3-fluorobenzyloxy)-phenyl)-amine and 4-chloro-6-iodoquinazoline. ¹HNMR (DMSO-d6) 9.77 (s, 1H); 8.92 (s, 1H); 8.50 (s, 1H); 8.06 (d, 1H);7.66 (d, 2H); 7.50 (d, 1H); 7.42 (m, 1H); 7.30-7.25 (m, 2H); 7.14 (m,1H); 7.03 (d, 2H); 5.13 (s, 2H), MS m/z 472 (M+1)

[0833]6-lodo-(4-(3-trifluoromethylbenzyloxy)-phenyl)-quinazolin-4-yl)amine

[0834] Prepared according to Procedure A from(4-(3-trifluoromethylbenzyloxy)-phenyl)-amine and4-chloro-6-iodoquinazoline. ¹H NMR (DMSO-d6) 9.2 (bs, 1H); 8.91 (s, 1H);8.37 (d, 1H); 7.89-7.72 (m, 8H); 7.19 (d, 2H); 5.30 (s, 2H).

[0835] 4-(4-(4-Phenoxyphenylamino)-quinolin-7-yl)thiazole-2-carbaldehyde

[0836] Prepared according to Procedure B from(4-phenoxyphenyl)-(7-iodoquinolin-4-yl)amine (2 g, 4.56 mmol),4-(tributylstannyl)thiazole-2-carbaldehyde (1.84 g, 4.56 mmol) anddichlorobis(triphenylphosphine)palladium (II) (0.74 g, 20 mol %) heatedat reflux overnight (18hrs) in dioxane (50 ml). The cooled solution wasfiltered through a plug of Celite®, concentrated and triturated withiso-hexane (3×20 ml). The resultant solid was purified via flash columnchromatography on silica gel, eluting with 5% methanol in chloroform.The purified product was isolated as a yellow solid (0.85 g, 44%). δH[²H₆] DMSO 10.10(1H, s), 9.30(1,bs), 8.90(1H, s), 8.50(2H, s&d),8.45(1H, d), 8.20(1H, d), 7.40(5H, bm), 7.10(4H, 2d), 6.80(1H, d).

[0837] 5-(4-(4-Phenoxyphenylamino)-quinolin-7-yl)thiazole-4-carbaldehyde

[0838] Prepared according to Procedure B from(4-phenoxyphenyl)-(7-iodoquinolin-4-yl)amine (0.876 g, 2 mmol),4-(1,3-dioxolan-2-yl)-5-tributylstannylthiazole (2.1 mmol), bis(triphenylphosphine) palladium (II) chloride (0.105 g, 0.15 mmol, 7.5mol %) and silver oxide (0.463 g, 2 mmol) heated under reflux undernitrogen for 18 hr. The reaction mixture was then filtered throughHarborlite® and the filtrate was concentrated. The product was purifiedon Bond Elut™ cartridge, eluting sequentially with dichloromethane,chloroform, diethyl ether and ethyl acetate. The ketal (0.385 g, 0.824mmol) was stirred at room temperature in a mixture of THF (10 ml) and 1N HCl (10 ml) for 2 hr. The suspension was basified with 2N NaOH (5 ml)and the THF was removed. The aqueous suspension was filtered and washedwith water to give the product as a yellow solid (0.346 g);m/z 424.

[0839]5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde

[0840] Prepared according to Procedure C from4-(4-benzyloxy-phenylamino)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazolin-4-yl)-amine(1.0 g, 2.1 mmol). The precipitate which formed was collected byfiltration and washed with acetone, then partitioned between ethylacetate, triethylamine and water. The organic phase was washed withwater, dried (magnesium sulphate) and the solvent was removed undervacuum. Trituration with iso-hexane/ethyl acetate gave the product as anorange solid (610 mg, 69%); δH [²H₆]-DMSO 10.05 (1H, b, NH), 9.62-(1H,s, CHO), 8.95 (1H, s, 5-H), 8.48 (1H, s, 2-H), 8.24 (1H, d, 7-H), 7.80(1H, d, 8-H), 7.70 (1H, d, furan 4-H), 7.59 (2H, d, 2′-H, 6′-H),7.48-7.25 (6H, m, 5 x Ph-H, furan 3-H), 7.02 (2H, m, 3′-H, 5′-H), 5.09(2H, s, CH₂); m/z 422 (M+1)⁺.

[0841]5-(4-(4-Benzyloxy-phenylamino)-7-methoxy-quinazolin-6-yl)-furan-2-carbaldehydeHydrochloride

[0842] Prepared according to Procedure C from(4-benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-methoxy-pyrido[3,4-d]pyrimidin-4-yl)-amine(0.301g, 0.60 mmol). After stirring 45 minutes, the resulting suspension wasfiltered and washed with ether to give 0.26 g of product as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ: 11.67(br s, 1H), 9.68(s, 1H),9.14(s, 1H), 8.78(s, 1H), 7.73(d, 1H), 7.52(d, 2H), 7.44(m, 3H), 7.39(m,3H), 7.32(m, 1H), 7.11(d, 2H), 5.14(s, 2H), 4.12(s, 3H). ESI-MS m/z452(M+1).

[0843]6-(5-(1.3-Dioxolan-2-yl)-furan-2-yl)-7-methoxy-quinazolin-4-yl-(4-benzenesulphonyl)phenyl-amine

[0844] Prepared according to Procedure B from4-(4-benzenesulphonyl)phenyl-7-methoxy-quinazolin-4-yl-amine and5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan. δ¹H NMR (400 MHz,DMSO-d₆) 10.36(s, 1H), 8.74(s, 1H), 8.58(s, 1H), 8.10(d, 2H), 7.93(m,4H), 7.62(m, 3H), 7.32(s, 1H), 7.04(d, 1H), 6.68(d, 1H), 5.99(s, 1H),4.09(m, 2H), 4.04(s, 3H), 3.95(m, 2H). ESI-MS m/z 530(M+1).

[0845] 5-(4-(4-Phenoxyphenylamino)-quinolin-7-yl)furan-2-carbaldehyde

[0846](4-Phenoxyphenyl)-(7-(5-(1,3-dioxolan-2-yl)furan-2-yl)-quinolin-4-yl)amine(1.4 g) was treated with 1M aqueous hydrochloric acid-tetrahydrofuran(60 ml, 1:1) in accordance with procedure C. Addition of 1 M aqueoussodium hydroxide solution to pH 10 followed by extraction with ethylacetate, drying (magnesium sulfate) and concentration to drynessafforded a yellow solid (1.2 g); δH [²H₆]DMSO 9.70 (1H, s), 9.10 (1H,s), 8.51 (2H, m), 8.35 (1H, s), 8.02 (1H, d), 7.73 (1H, d), 7.57 (1H,d), 7.42 (4H, m), 7.22-7.04 (5H, m), 6.88 (1H, d); m/z 407 (M+1)⁺.

[0847]5-(7-Methoxy-4-(4-benzenesulphonyl)phenylamino-quinazolin-6-yl)-furan-2-carbaldehydeHydrochloride

[0848] Prepared according to Procedure C from6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-methoxy-quinazolin-4-yl-(4-benzenesulphonyl)phenyl-amine.δ¹H NMR (400 MHz, DMSO-d₆) 11.54(br s, 1H), 9.68(s, 1H), 9.13(s, 1H),8.83(s, 1H), 7.95-8.06(m, 6H), 7.72(d, 1H), 7.68(m, 1H), 7.62(m, 2H),7.46(s, 1H), 7.39(d, 1H), 4.12(s, 3H). ESI-MS m/z 486(M+1).

[0849]5-(4-(4-Benzyloxy-phenylamino)-7-fluoro-quinazolin-6-yl)-furan-2-carboxaldehydeHydrochloride

[0850] Prepared according to Procedure C from a stirred solution of(4-7-benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-fluoro-quinazolin-4-yl)-amine(0.51 grams, 1.1 mmol) in 20 ml of THF was added 5 ml of 1 N HCl. Afterstirring for 90 minutes, the resultant suspension was filtered andwashed with diethyl ether (200 ml) to yield, after drying under vacuum,a yellow solid (0.32 grams, 61% yield). δ¹H NMR (400 MHz, DMSO-d₆)11.52(s, 1H), 9.70(s, 1H), 9.25(d, 1H),8.76(s, 1H), 7.76(m, 2H), 7.55(d,2H), 7.45(d, 2H), 7.33(m, 4H), 7.11 (d, 2H), 5.14(s, 2H). ESI-MS m/z440(M+1).

[0851]5-(4-(1-Benzyl-1H-indazol-5-ylamino)-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehydeHydrochloride

[0852] Prepared according to Procedure C from(1-benzyl-1H-indazol-5-ylamino)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-fluoro-quinazolin-4-yl)-amine.δ¹H NMR (400 MHz, DMSO-d₆) 11.68(s, 1H),9.71 (s, 1H), 9.28(d, 1H),8.74(s, 1H), 8.12(s, 1H), 8.02(s, 1H), 7.78(m, 3H), 7.58(m, 2H), 7.3(m,5H), 5.65(s, 2H). ESI-MS m/z 462(M−1).

[0853]5-(4-(4-Benzenesulphonylphenylamino)-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehydehydrochloride

[0854] Prepared according to Procedure C from6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-fluoro-quinazolin-4-yl-(4-benzenesulphonyl)phenyl-amine.¹H NMR (400 MHz, DMSO-d₆) δ: 10.96(s, 1H), 9.7(s, 1H), 9.16(d, 1H),8.72(s, 1H), 8.07(d, 2H), 7.96(m, 4H), 7.75(m, 2H), 7.64(m, 3H), 7.29(m,1H. ESI-MS m/z 472(M−1).

[0855]5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehydeHydrochloride

[0856] Prepared according to Procedure C from4-(4-benzyloxyphenylamino)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazolin-4-yl)-amine(6.70 g, 14.4 mmol). The resulting precipitate was collected byfiltration and washed with water to give the hydrochloride salt as ayellow solid (6.50 g, 14.1 mmol, 98%); δH [²H₆]DMSO 12.15 (1H, s), 9.69(1H, s) 9.58 (1H, s), 8.88 (1H, s), 8.50 (1H, dd), 8.02 (1H, d), 7.77(1H, d), 7.62-7.74 (3H, m), 7.31-7.52 (5H, m), 7.15 (2H, d), 5.17 (2H,s).

[0857](4-Phenoxyphenyl)-(7-(5-(1,3-dioxolan-2-yl)furan-2-yl)-quinolin-4-yl)amine

[0858] (4-Phenoxyphenyl)-(7-iodo-quinolin-4-yl)amine (2 g) was treatedwith 2-to (tributylstannyl)-5-(1,3-dioxolan-2-yl)-furan (2.16 g) andtetrakis (triphenylphosphine) palladium (O) (0.26 g) indimethylacetamide (20 ml) in accordance with Procedure B. Purificationvia column chromatography, eluting with ethyl acetate, followed bytrituration with diethylether afforded a yellow solid (1.4 g); δH[²H₆]DMSO 9.10 (1H, s), 8.45 (2H, m), 8.13 (1H, s), 7.96 (1H, d), 7.41(4H, m), 7.22 (1H, d), 7.20-7.03 (5H, m), 6.83 (1H, d), 6.75 (1H, d),6.02 (1H, s), 4.13 (2H, m), 4.01 (2H, m); m/z 451 (M+1)⁺.

[0859] (1-Benzyl-1H-indazol-5-yl)-(6-bromoquinazolin-4-yl)-amine

[0860] Prepared according to Procedure A from6-bromo-4-chloroquinazoline (5.0 g) and 5-amino-1-benzyl-1H-indazole(5.0 g) in acetonitrile (100 ml) at 100° C. The resulting precipitatewas treated with triethylamine in ethyl acetate and water to give thetitle compound as a yellow solid, (7.37 g); δH [²H₆]-DMSO 9.93(1H, s),8.82 (1H, d), 8.52(1H, s), 8.19(1H, s), 8.09(1H, s), 7.92(1H, dd),7.65(3H, m), 7.25(5H, m), 5.62(2H, s).

[0861] (1-Benzyl-1H-indazol-5-yl)-(6-iodoquinazolin-4-yl)-amineHydrochloride

[0862] Prepared according to Procedure A from 4-chloro-6-iodoquinazoline(5.8 g) was treated with 5-amino-1-benzyl-1H-indazole (3.90 g) inacetonitrile (500 ml) at reflux under N₂ for 18 hours. Subsequentcooling and filtration gave the title compound (8.26 g); m/z (M+1)⁺478.

[0863](1-Benzyl-1H-indazol-5-yl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazolin-4-yl)-amine

[0864] Prepared according to Procedure B from(1-benzyl-1H-indazol-5-yl)-(6-bromoquinazolin-4-yl)-amine (4.3 g),2-(tributylstannyl)-5-(1,3-dioxolan-2-yl)-furan (J. Chem. Soc., ChemCommun., (1988), 560) (10 g) and 1,4-bis(diphenylphosphino) palladium(II) chloride (1 g) in dioxane. The solvent was removed in vacuo and theresidue chromatographed on silica. Subsequent trituration gave the titlecompound δH [²H₆]-DMSO 10.13 (1H, s), 8.85 (1H, s), 8.54 (1H, s), 8.20(3H, m), 7.80 (3H, m), 7.30 (5H, m), 7.13 (1H, d), 6.79 (1H, d), 6.04(1H, s), 5.71 (2H, s), 4.15 (4H, m).

[0865](1-Benzyl-1H-indazol-5-yl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-methoxy-quinazolin-4-yl)-amine

[0866] Prepared according to Procedure B from(1-benzyl-1H-indazol-5-yl)-7-methoxy-6-trifluoromethanesulphonyl-quinazolin-4-yl)-amineand 2-(tributylstannyl)-5-(1,3-dioxolan-2-yl)-furan. ¹H NMR (400 MHz,DMSO-d₆) δ: 10.07(s, 1H), 8.75(s, 1H), 8.42(s, 1H), 8.09(s, 2H), 7.64(m,2H), 7.2-7.3(m, 6H), 7.01 (d, 1H), 6.68(d, 1H), 5.99(s, 1H), 5.64(s,2H), 4.09(m, 2H), 4.03(s, 3H), 3.94(m, 2H). ESI-MS m/z 520(M+1).

[0867]5-(4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-6-yl)-furan-2-carbaldehydeHydrochloride

[0868] Prepared according to Procedure C from(1-benzyl-1H-indazol-5-yl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazolin-4-yl)-amine(2.0 g). The resulting precipitate was filtered, washed with water anddried at 60° C. in vacuo to give the product as a yellow solid (1.80 g,3.73 g, 91%); δH [²H₆]-DMSO 12.30 (1H, s), 9.79 (1H, s), 9.62 (1H, s),8.85 (1H, s), 8.62 (1H, m), 8.31 (1H, s), 8.19 (1H, m), 8.10 (1H, d),7.90 (2H, m), 7.78 (2H, m), 7.40 (5H, m), 5.80 (2H, s).

[0869]5-(4-(1-Benzyl-1H-indazol-5-yl)-7-methoxy-quinazolin-6-yl)-furan-2-carbaldehydeHydrochloride

[0870] Prepared according to Procedure C from(1-benzyl-1H-indazol-5-yl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-methoxy-quinazolin-4-yl)-amine.δH NMR (400 MHz, DMSO-d₆): 11.94(br s, 1H), 9.68(s, 1H), 9.20(s, 1H),8.79(s, 1H), 8.19(s, 1H), 7.97(d, 1H), 7.81 (d, 1H), 7.74(d, 1H),7.57(m, 1H), 7.44(s, 1H), 7.41 (d, 1H), 7.30(m, 2H), 7.24(m, 3H),5.68(s, 2H), 4.13(s, 3H). ESI-MS m/z 476(M+1).

[0871] 7-Iodoquinazolin-4-one

[0872] 7-Amino-quinazolin-4-one (R. Dempsy and E. Skito, Biochemistry,30, 1991, 8480) (1.61 g) was suspended in 6N HCl (20 ml) and cooled inan ice bath. A solution of sodium nitrite (0.75 g) in water (10 ml) wasadded dropwise over 15 minutes. After a further 10 minutes, a solutionof potassium iodide (1.66 g) in water (5 ml) was added dropwise. Themixture was warmed to 20° C. and after 3 hours partitioned between ethylacetate and sodium thiosulphate. The organic phase was dried andconcentrated in vacuo to give the title compound (0.485 g); m/z (M+1+)271.

[0873] 4-Chloro-7-iodoquinazoline

[0874] 7-Iodoquinazolin-4-one (0.46 g) was treated with phosphorousoxychloride (5 ml) at reflux under nitrogen for 2 hours. The mixture wascooled, evaporated and it partitioned between saturated aqueous sodiumcarbonate and ethyl acetate. The organic phase was dried andconcentrated in vacuo to give the title compound (0.43 g); m/z (M+1+)291.

[0875] (1-Benzyl-1H-indazol-5-yl)-(7-iodoquinazolin-4-yl)-amineHydrochloride

[0876] Prepared according to Procedure A from 4-Chloro-7-iodoquinazoline(0.42 g) and 1-benzyl-1H-indazol-5-ylamine (0.323 g) in acetonitrile (20ml) at reflux under nitrogen for 18 hours. The mixture was cooled andfiltered to give the title compound (0.57 g); m/z (M+1+) 478.

[0877](1-Benzyl-1H-indazol-5-yl)-[7-(5-(1,3-dioxolan-2-yl)-furan-2-yl)quinazolin-4-yl]amineHydrochloride

[0878] Prepared according to Procedure B from(1-benzyl-1H-indazol-5-yl)-(7-iodoquinazolin-4-yl)-amine hydrochlorideand 5-(1,3-dioxolan-2-yl)-2-(tri-n-butylstannyl)furan; tic Rf, 0.25(100% EtOAc on silica); m/z (M+1+) 490.

[0879]5-[4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-7-yl]-furan-2-carbaldehyde

[0880] Prepared according to Procedure C from(1-benzyl-1H-indazol-5-yl)-[7-(5-(1,3-dioxolan-2-yl)furan-2-yl)quinazolin-4-yl]-aminehydrochloride (0.27 g) stirred in THF:2N HCl (2:1, 15 ml) at 20° C. for1 hour. Filtration gave5-[4-(1-benzyl-1H-indazol-5-ylamino)-quinazolin-7-yl]-furan-2-carbaldehyde,which was not further characterised.

[0881](4-Benzyloxy-phenyl)-(6-((5-(2-methylthio-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amineDihydrochloride

[0882]5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde(100 mg) and (methylthio)ethylamine (80 mg) in dichloromethane (5 ml)were reacted together as in Procedure D. Purification using columnchromatography, followed by conversion to the hydrochloride salt gave ayellow solid (61 mg). m/z 497 (M+1)⁺.

[0883](6-Chloropyrido[3,4-d]pyrimidin-4-yl)-(4-(4-fluorobenzyloxy)-phenyl)-amine

[0884] 4,6-Dichloro-pyrido[3,4-d]pyrimidine (1 g) and4-(4-fluorobenzyloxy)aniline (1.08 g) in acetonitrile (70 ml) werereacted together as in Procedure A. The product was collected byfiltration as a yellow solid (1.83 g); m/z 381 (M+1)⁺.

[0885](6-(5-(1,3-Dioxolan-2-yl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-(4-(4-fluorobenzyloxy)-phenyl)-amine

[0886](6-Chloropyrido[3,4-d]pyrimidin-4-yl)-(4-(4-fluorobenzyloxy)-phenyl)-amine(1.82 g) and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)-furan (3.75 g) indioxan (40 ml) were reacted together as in Procedure B. The mixture wasevaporated and the residue suspended in dichloromethane. This was thenfiltered through celite and the solvent evaporated. The gummy residuewas then triturated with hexane giving a beige solid (1.21 g); m/z 485(M+1)⁺.

[0887]5-(4-(4-(4-Fluorobenzyloxy)-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde

[0888](6-(5-(1,3-Dioxolan-2-yl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-(4-(4-fluorobenzyloxy)-phenyl)-amine(500 mg) was treated with acid as in Procedure C. The product wascollected by filtration as a red solid (330 mg); m/z 441 (M+1)⁺.

[0889](4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-(2-(methylthio)-ethylaminomethyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine

[0890]5-(4-(4-(4-Fluorobenzyloxy)-phenyl)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde(110 mg) and (methylthio)ethylamine (0.06 ml) in dichloromethane (5 ml)were reacted together as in Procedure D. Purification using a Bond Elut™cartridge gave a yellow oil (52 mg); m/z 516 (M+1)⁺.

[0891](6-Chloropyrido[3,4-d]pyrimidin-4-yl)-(4-(3-fluorobenzyloxy)-phenyl)-amine

[0892] 4,6-Dichloro-pyrido[3,4-d]pyrimidine (1 g) and4-(3-fluorobenzyloxy)aniline (1.08 g) in acetonitrile (70 ml) werereacted together as in Procedure A. The product was collected byfiltration as a yellow solid (1.86 g); m/z 381 (M+1)⁺.

[0893](6-(5-(1,3-Dioxolan-2-yl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-(4-(3-fluorobenzyloxy)-phenyl)-amine

[0894](6-Chloropyrido[3,4-d]pyrimidin-4-yl)-(4-(3-fluorobenzyloxy)-phenyl)-amine(1.85 g) and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)-furan (3.82 g) indioxan (40 ml) were reacted together as in Procedure B. The mixture wasevaporated and the residue suspended in dichloromethane. This was thenfiltered through Celite® and the solvent evaporated. The gummy residuewas then triturated with hexane giving a beige solid (1.74 g); m/z 485(M+1)⁺.

[0895]5-(4-(4-(3-Fluorobenzyloxy)-phenylamino)-pyrido[3-4-d]pyrimidin-6-yl)-furan-3-carbaldehyde

[0896](6-Chloropyrido[3,4-d]pyrimidin-4-yl)-(4-(3-fluorobenzyloxy)-phenyl)-amine(1 g) and 5-(tributylstannyl)-furan-3-carbaldehyde (J. Org. Chem.(1992), 57(11), 3126-31) (1.84 g) in dioxan (35 ml) were reactedtogether as in Procedure B. The solvent was evaporated and the residuesuspended in dichloromethane. The mixture was filtered through Celite®and then evaporated. The residue was triturated with hexane giving abeige solid (1 g); m/z 441 (M+1)⁺.

[0897]5-(4-(4-(3-Fluorobenzyloxy)-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde

[0898](6-(5-(1,3-Dioxolan-2-yl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-(4-(3-fluorobenzyloxy)-phenyl)-amine(500 mg) was treated with acid as in Procedure C. The product wascollected by filtration as a beige solid (251 mg); ml/z 441 (M+1)⁺.

[0899](4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-(2-(methylthio)-ethylaminomethyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine

[0900](5-(4-(4-(3-Fluorobenzyloxy)-phenyl)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde(125 mg) and (methylthio)ethylamine (0.08 ml) in dichloromethane (5 ml)were reacted together as in Procedure D. Purification using a Bond Elut™cartridge gave a yellow oil (80 mg); m/z 516 (M+1)⁺.

[0901](4-Benzenesulphonyl-phenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine

[0902] Prepared according to Procedure A from 4-benzenesulphonylaniline(Helv. Chim. Acta., 1983, 66 (4), 1046) and4,6-dichloropyrido[3,4-d]pyrimidine; δH [²H₆]-DMSO 9.09 (1H, s),8.80-8.88 (2H, m), 8.19 (2H, d), 7.94-8.09 (4H, m), 7.53-7.20 (3H, m);m/z (M+1)⁺397.

[0903](4-Benzenesulphonyl-phenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine

[0904](4-Benzenesulphonyl-phenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine(3.67 g) j>and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)-furan (6.9 g)were reacted together in dioxan (100 ml) as in Procedure B. Purificationby column chromatography gave a cream solid (2.59 g); δH [²H₆]DMSO 10.6(1H, s) 9.26 (1H, s) 8.82 (1H, s) 8.78 (1H, s) 8.25 (2H, d) 8.0-8.3 (4H,d+m) 7.65-7.8 (3H, m) 7.21 (1H, d) 6.82 (1H, d) 6.09 (1H, s) 4.0-4.2(4H, m); m/z 501 (M+1)⁺.

[0905]5-(4-(4-Benzenesulphonyl-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)furan-2-carbaldehydeHydrochloride

[0906](4-Benzenesulphonyl-phenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine(2.59 g) was treated with acid in tetrahydrofuran (70 ml) as inProcedure C. The compound was obtained as a yellow solid afterfiltration (1.57 g); δH [²H₆]DMSO 9.7 (1H, s) 9.26 (1H, s) 9.11 (1H, s)8.82 (1H, s) 8.19 (1H, s) 8.15 (1H, s) 7.95-8.03 (4H, m) 7.75 (1H, d)7.58-7.7 (3H, m) 7.49 (1H, s); m/z 457 (M+1)⁺.

[0907](4-Benzenesulphonyl-phenyl)-(6-(5-((2-methylthio-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amineDihydrochloride

[0908]5-(4-((4-Benzenesulphonyl-phenyl)amino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde(250 mg) and (methylthio)ethylamine (185 mg)) in dichloromethane (5 ml)were reacted together as in Procedure D. Purification using a Bond Elut™cartridge, gave a yellow solid (245 mg), 70 mg of which was converted tothe hydrochloride salt, (yellow solid, 68 mg); m/z 532 (M+1)⁺.

[0909](4-Benzyloxy-phenyl)-(6-(3-(1,3-dioxolan-2-yl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine

[0910] (4-Benzyloxy-phenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine(1.4 g) and 3-(1,3-dioxolan-2-yl)-phenyl-tributylstannane (3.08 g) [A.Lee and W -C. Dai, Tetrahedron (1997), 53(3), 859-868] in dioxan (30 ml)were reacted together as in Procedure B. The mixture was evaporated andthe residue suspended in dichloromethane. This was then filtered throughcelite and the solvent evaporated. The gummy residue was then trituratedwith hexane giving a beige solid. This material was further purified bycolumn chromatography, giving a brown foam (252 mg); m/z 477 (M+1)⁺.

[0911]3-(4-((4-Benzyloxy-phenyl)-amino)-pyrido[3,4-d]pyrimidin-6-yl)-benzaldehyde

[0912](4-(4-Benzyloxy-phenyl)-6-(3-(1,3-dioxolan-2-yl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine(250 mg) was treated with acid as in Procedure C. The product wasisolated by filtration as a brown solid (115 mg); m/z 433 (M+1)⁺.

[0913]4-(4-(4-Benzyloxy-phenyl)-amino)-quinazolin-6-yl)-thiazol-2-carbaldehyde

[0914] (4-Benzyloxy-phenyl)-(6-iodo-quinazolin-4-yl)-amine (2 g) and4-(tributylstannyl)-thiazol-2-carbaldehyde (3.28 g) in dioxan (25 ml)were reacted together as in Procedure B. The mixture was evaporated andthe residue purified using column chromatography, giving a yellow solid(849 mg); m/z 439 (M+1)⁺.

[0915] Other suitable intermediates prepared by analogous methods tothose described above are:

[0916](4-Benzyloxy-3-chlorophenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0917](4-(3-Fluoro-benzyloxy)-3-chlorophenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0918](4-Benzyloxy-3-trifluoromethylphenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0919](4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0920](4-Benzyloxy-3-bromophenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0921](4-(3-Fluoro-benzyloxy-3-bromophenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0922](4-Benzyloxy-3-iodophenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0923](4-(3-Fluoro-benzyloxy-3-iodophenyl)-6-(chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0924](4-Benzyloxy-3-fluorophenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0925](4-(3-Fluoro-benzyloxy-3-fluorophenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[0926]5-((4-Benzyloxy-3-chlorophenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde;

[0927]5-((4-(3-Fluoro-benzyloxy)-3-chlorophenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde;

[0928]5-((4-Benzyloxy-3-trifluoromethylphenylamino)-pyrido[3,4-d]6-yl)-furan-2-carbaldehyde;

[0929]5-((4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde;

[0930]5-((4-Benzyloxy-3-bromophenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde;

[0931]5-((4-(3-Fluoro-benzyloxy-3-bromophenylamino)-pyrido[3,4-d]6-yl)-furan-2-carbaldehyde;

[0932]5-((4-Benzyloxy-3-iodophenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde;

[0933]5-((4-(3-Fluoro-benzyloxy-3-iodophenylamino)-pyrido[3,4-d]6-yl)-furan-2-carbaldehyde;

[0934]5-((4-Benzyloxy-3-fluorophenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carboxaldehyde;

[0935]5-((4-(3-Fluoro-benzyloxy-3-fluorophenylamino)-pyrido[3,4-d]6-yl)-furan-2-carbaldehyde;

[0936]N-[4-(benzyloxy)-3-chlorophenyl]-7-fluoro-6-chloro-4-quinazolinamine;

[0937]N-[4-(3-Fluoro-benzyloxy)-3-chlorophenyl]-7-fluoro-6-chloro-4-quinazolinamine

[0938]N-[4-Benzyloxy-3-trifluoromethylphenyl]-7-fluoro-6-chloro-4-quinazolinamine

[0939]N-[4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl]-7-fluoro-6-chloro-4-quinazolinamine;

[0940]N-[4-Benzyloxy-3-bromophenyl]-7-fluoro-6-chloro-4-quinazolinamine;

[0941]N-[4-(3-Fluoro-benzyloxy-3-bromophenyl]-7-fluoro-6-chloro-4-quinazolinamine;

[0942] N-[4-Benzyloxy-3-iodophenyl]-7-fluoro-6-chloro-4-quinazolinamine;

[0943]N-[4-(3-Fluoro-benzyloxy-3-iodophenyl]-7-fluoro-6-chloro-4-quinazolinamine;

[0944]N-[4-Benzyloxy-3-fluorophenyl]-7-fluoro-6-chloro-4-quinazolinamine;

[0945]N-[4-(3-Fluoro-benzyloxy-3-fluorophenyl]-7-fluoro-6-chloro-4-quinazolinamine;

[0946]N-[1-(3-fluorobenzyl-1H-indazol-5-yl]-7-fluoro-6-chloro-4-quinazolinamine;

[0947]5-(4-[4-(Benzyloxy)-3-chlorophenylamino]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde;

[0948]5-(4-[4-(3-Fluoro-benzyloxy)-3-chlorophenyl]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde;

[0949]5-(4-[4-Benzyloxy-3-trifluoromethylphenyl]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde;

[0950]5-(4-[4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde;

[0951]5-(4-[4-Benzyloxy-3-bromophenyl]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde;

[0952]5-(4-[4-(3-Fluoro-benzyloxy-3-bromophenyl]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde;

[0953]5-(4-[4-Benzyloxy-3-iodophenyl]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde;

[0954]5-[4-(3-Fluoro-benzyloxy-3-iodophenyl]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde;

[0955]5-[4-Benzyloxy-3-fluorophenyl]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde

[0956]5-(4-(3-Fluoro-benzyloxy-3-fluorophenyl]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde;

[0957]5-(4-[1-(3-Fluorobenzyl-1H-indazol-5-ylamino]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde;

EXAMPLES Example 1

[0958]

[0959](4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amineDihydrochloride

[0960](4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-(2-(methylthio)-ethylaminomethyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine(52 mg) in methanol (9 ml) and water (3 ml) was treated with Oxone™ (99mg) at room temperature for 2 days. The mixture was then partitionedbetween aqueous sodium carbonate solution and dichloromethane. The driedorganic phase was evaporated and the residue purified by Bond Elut™cartridge, followed by conversion to the hydrochloride salt, giving ayellow solid (31 mg); δH [²H₆]DMSO 9.9 (1H, bs) 9.25 (1H, s) 8.8 (1H, s)7.9 (2H, d) 7.5-7.6 (2H, m) 7.1-7.3 (5H, m) 6.9 (1H, d) 5.2 (2H, s) 4.5(2H, s) 3.6-3.8 (4H, m) 3.2 (3H, s); m/z 548 (M+1)⁺.

Example 2

[0961]

[0962] (4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine Dihydrochloride

[0963](4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-(2-(methylthio)-ethylaminomethyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine(80 mg) in methanol (9 ml) and water (3 ml) was treated with Oxone™ (153mg) at room temperature for 2 days. The mixture was then partitionedbetween aqueous sodium carbonate solution and dichloromethane. The driedorganic phase was evaporated and the residue purified by Bond Elut™cartridge, followed by conversion to the hydrochloride salt, giving ayellow solid (69 mg); δH [²H₆]DMSO 9.8 (1H, bs) 9.4 (1H, s) 9.3 (1H, s)8.7 (1H, s) 7.8 (2H, d) 7.3-7.4 (2H, m) 7.0-7.3 (5H, m) 6.8 (1H, d) 5.3(2H, s) 4.4 (2H, s) 3.5-3.7 (4H, m) 3.1 (3H, s); m/z 548 (M+1)⁺.

Example 3

[0964]

[0965](4-Benzenesulphonyl-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amineDihydrochloride

[0966](4-Benzenesulphonyl-phenyl)-(6-(5-((2-methylthio-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine(162 mg) in methanol (20 ml) and water (10 ml) was treated with Oxone™(345 mg) at room temperature for 18h. The mixture was then evaporatedand the residue purified by Bond Elut™ cartridge, followed by conversionto the hydrochloride salt, giving a yellow solid (55 mg); δH [²H₆]DMSO9.8 (1H, bs) 9.3 (1H, s) 9.2 (1H, s) 8.8 (1H, s) 8.3 (2H, d) 7.9-8.0(4H, m) 7.6-7.7 (3H, m) 7.2 (1H, d) 6.8 (1H, d) 4.4 (2H, s) 3.3-3.7 (4H,m) 3.1 (3H, s); m/z 564 (M+1)⁺.

Example 4

[0967]

[0968](4-Benzyloxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amineDihydrochloride.

[0969]3-((4-(4-Benzyloxy-phenyl)-amino)-pyrido[3,4-d]pyrimidin-6-yl)-benzaldehyde(106 mg) and 2-methanesulphonyl-ethylamine (111 mg) in dichloromethane(5 ml) were reacted together as in Procedure D. Purification usingcolumn chromatography, followed by conversion to the hydrochloride salt,gave a yellow solid (66 mg); δH [²H₆]DMSO 9.6 (2H, bs) 9.3 (1H, s) 9.2(1H, s) 8.65 (1H, s) 8.55 (1H, s) 8.3 (1H, m) 7.7-7.8 (2H, m) 7.6 (2H,m) 7.25-7.45 (4H, m) 7.0 (2H, d) 5.1 (2H, s) 4.3 (2H, s) 3.2-3.8 (4H, m)3.1 (3H, s). m/z 540 (M+1)⁺.

Example 5

[0970]

[0971](4-Benzyloxyphenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amineDihydrochloride

[0972]5-((4-(4-Benzyloxyphenyl)-amino)-quinazolin-6-yl)-furan-2-carbaldehyde(200 mg) and 2-methanesulphonyl-ethylamine (215 mg) in dichloromethane(10 ml) were reacted together as in Procedure D. Purification usingcolumn chromatography, followed by conversion to the hydrochloride salt,gave a yellow solid (121 mg); δH [²H₆]DMSO 9.7 (1H, s) 8.9 (1H, s) 8.4(1H, d) 8.0 (1H, d) 7.75 (2H, d) 7.3-7.5 (7H, m) 7.1 (2H, d) 6.85 (1H,d) 5.2 (2H, s) 4.4 (2H, s) 3.2-3.7 (4H, m) 3.1 (3H, s); m/z 529(M+1)⁺.

Example 6

[0973]

[0974](4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amineDihydrochloride

[0975]5-(4-(4-(3-Fluorobenzyloxy)-phenyl)-pyrido[3,4-d]pyrimidin-6-yl)-furan-3-carbaldehyde(300 mg) and 2-methanesulphonyl-ethylamine (335 mg) in dichloromethane(15 ml) were reacted together as in Procedure D. Purification using aBond Elut™ cartridge, followed by conversion to the hydrochloride salt,gave a yellow solid (110 mg); δH [²H₆]DMSO 9.8 (2H, br) 9.3 (1H, s) 9.0(1H, s) 8.8 (1H, s) 8.2 (1H, s) 8.0 (1H, s) 7.1-7.8 (7H, m) 7.0 (1H, s)5.2 (2H, s) 4.1-4.3 (4H, brm) 3.3-3.5 (2H, bs) (hidden under H₂0 peak)3.2 (3H, s); m/z 548(M+1)⁺.

Example 7

[0976]

[0977] (4-Benzyloxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-4-yl)-quinazolin-4-yl)-amineDihydrochloride

[0978]4-(4-(4-Benzyloxy-phenyl)-amino)-quinazolin-6-yl)-thiazol-2-carbaldehyde(70 mg) and 2-methanesulphonyl-ethylamine (79 mg) in dichloromethane (10ml) were reacted together as in Procedure D. Purification using a BondElut™ cartridge, followed by conversion to the hydrochloride salt, gavea yellow solid (59 mg); δH [²H₆]DMSO 12.3 (1H, s) 10.0 (1H, s) 8.95 (1H,s) 8.8 (1H, s) 8.75 (1H, d) 7.4-7.6 (6H, m) 7.2 (2H, d) 5.25 (2H, s) 4.8(2H, s) 3.6-3.8 (4H, m) 3.2 (3H, s); m/z 546(M+1)⁺.

Example 8

[0979]

[0980]N-{4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

[0981] Prepared according to Procedure D from5-(4-{4-(3-fluorobenzyloxy)anilino}-6-quinazolinyl)-furan-2-carbaldehyde(0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). ¹H NMR 400 MHz(DMSO-d6) 9.40 (s, 1H); 8.67 (s, 1H); 8.30 (d, 1H); 7.86 (d, 1H); 7.75(d, 2H); 7.43 (m, 1H); 7.30-7.21 (m, 3H); 7.15 (m, 1H); 7.07 (d, 2H);6.80 (d, 1H); 5.15 (s, 2H); 4.40 (s, 2H); 3.65 (m, 2H); 3.40 (m, 2H);3.11 (s, 3H); MS m/z 547 (M+1).

Example 9

[0982]

[0983]N-{14-[(3-fluorobenzyl)oxy]-3-methoxyphenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

[0984] Prepared according to Procedure D from5-(4-{3-methoxy-4-(3-fluorobenzyloxy)anilino}-6-quinazolinyl)-furan-2-carbaldehyde(0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). ¹H NMR 400 MHz(DMSO-d6) 9.22 (s, 1H); 8.78 (s, 1H); 8.31 (d, 1H); 7.88 (d, 1H);7.50-7.08 (m, 8H); 6.84 (d, 1H); 5.13 (s, 2H); 4.42 (s, 2H); 3.80 (s,3H); 3.60 (m, 2H); 3.40 (m, 2H, obscured by water peak); 3.10 (s, 3H);MS m/z 577 (M+1).

Example 10

[0985]

[0986]N-[4-(benzyloxy)phenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

[0987] Prepared in a similar manner to Procedure D from5-(4-(4-benzyloxy-phenylamino)-7-methoxy-quinazolin-6-yl)-furan-2-carbaldehydehydrochloride(78 mg, 0.16 mmol), 2-methanesulphonylethylamine(33 mg,0.27 mmol), acetic acid(15 mg, 0.25 mmol) and triethylamine(18 mg, 0.18mmol) in 3 ml of 1,2-dichloroethane added to sodiumtriacetoxyborohydride(102 mg, 0.48 mmol) portionwise over a two dayperiod. The reaction mixture was stirred four days and then partitionedbetween 10 ml of 0.5M NaHCO₃ solution and 50 ml of ethyl acetate. Theorganic solution was dried with Na₂SO₄ and concentrated in vacuo. Theresidue was chromatographed on silica gel with methanol/methylenechloride(1:49 to 2:48). The resulting solid was crystallized from asmall volume of ethyl acetate, suspended in ether and filtered to give43 mg of product as a pale yellow solid. δ¹H NMR (400 MHz, DMSO-d₆)9.78(s, 1H), 8.73(s, 1H), 8.42(s, 1H), 6.64(d, 2H), 7.47(m, 2H), 7.40(m,2H), 7.33(m, 1H), 7.25(s, 1H), 7.04(d, 2H), 6.98(d, 1H), 6.46(d, 1H),5.12(s, 2H), 4.04(s, 3H), 3.86(s, 2H), 3.28(t, 2H), 3.01 (s, 3H),2.99(t, 2H). ESI-MS m/z 559(M+1).

Example 11

[0988]

[0989]N-[4-(benzyloxy)phenyl]-6-[4-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

[0990] Prepared according to Procedure D from5-(4-{4-benzyloxyanilino}-6-quinazolinyl)-furan-3-carbaldehyde (0.6equiv) and 2-methanesulphonyl-ethylamine (1 equiv). ¹HNMR 400 MHz,d6DMSO 9.51 (bs, 2H), 9.11 (s, 1H), 8.79 (s, 1H), 8.29 (d, 1H), 8.06 (s,1H), 7.90 (d, 1H), 7.60 (d, 2H), 7.5-7.3 (m, 5H), 7.11 (d, 2H), 5.14 (s,2H), 4.14 bs, 2H), 3.6-3.5 (m, 3H), 3.12 (s, 3H); MS m/z 529 (M+1).

Example 12

[0991]

[0992]N-{4-[(3-fluorobenzyl)oxy]-3-methoxyphenyl}-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine

[0993] Prepared according to Procedure F from6-iodo-(4-(3-fluorobenzyloxy)-3-methoxypheny)quinazolin-4-ylamine (1equiv), 2-ethoxyvinyl-tributylstannane (1-equiv), N-bromosuccinimide (1equiv) andN-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide (1equiv).¹H NMR 400 MHz (CD₃OD) 9.40 (s, 1H); 8.79 (s, 1H); 8.76 (d, 1H);8.38 (s, 1H); 7.89 (d, 1H); 7.50 (s, 1H); 7.40 (t, 1H); 7.34 (m, 1H);7.27 (d, 1H); 7.22 (d, 1H); 7.08 (d, 1H); 7.03 (t, 1H); 5.19 (s, 2H);4.81 (s, 2H); 3.85 (m, 2H); 3.75 (m, 2H); 3.10 (s, 3H); MS m/z 594(M+1)⁺, 592 (m−1)⁻.

Example 13

[0994]

[0995]N-{4-[(3-bromobenzyl)oxy]phenyl}-6-[2-{[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine.

[0996] Prepared according to Procedure F from6-iodo-(4-(3-bromobenzyloxy)-phenyl)quinazolin-4-ylamine (1 equiv),2-ethoxyvinyl-tributylstannane (1 equiv), N-bromosuccinimide (1 equiv)and N-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide(1 equiv). ¹H NMR 400 MHz (CD₃OD) 9.40 (s, 1H); 8.78 (d, 1H); 8.74 (d,1H); 8.34 (s, 1H); 7.88 (d, 1H); 7.65 (d, 2H); 7.62 (s, 1H); 7.48 (d,1H); 7.30 (d, 1H); 7.30 (m, 1H); 7.12 (d, 2H); 5.16 (s, 2H); 4.80 (s,2H); 3.85 (m, 2H); 3.75 (m, 2H); 3.10 (s, 3H); MS m/z 624, 626 (M+1)⁺,622, 624 (m−1)⁻.

Example 14

[0997]

[0998]N-{4-[(3-fluorobenzyl)oxy]phenyl}-6-[2-{[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine

[0999] Prepared according to Procedure F from6-iodo-(4-(3-fluorobenzyloxy)-phenyl)-quinazolin-4-ylamine and (1equiv), 2-ethoxyvinyl-tributylstannane (1 equiv), N-bromosuccinimide (1equiv) andN-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide (1equiv). ¹H NMR 400 MHz (CD₃OD) 9.44 (s, 1H); 8.79 (s, 1H); 8.76 (d, 1H);8.37 (s, 1H); 7.90 (d, 1H); 7.74 (d, 1H); 7.53 (d, 1H); 7.46 (d, 2H);7.38 (m, 2H); 7.32 (d, 1H); 7.24 (d, 1H); 5.21 (s, 2H); 4.82 (s, 2H);3.85 (m, 2H); 3.77 (m, 2H); 3.11 (s, 3H); MS m/z 564 (M+1)⁺, 562 (m−1)⁻.

Example 15

[1000]

[1001]N-[4-(benzyloxy)-3-fluorophenyl]-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine

[1002] Prepared according to Procedure F from6-iodo-(4-benzyloxy)-3-fluorophenyl)quinazolin-4-ylamine andN-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide (1equiv), 2-ethoxyvinyl-tributylstannane (1 equiv), N-bromosuccinimide (1equiv) andN-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide (1equiv). ¹H NMR 400 MHz (CD₃OD) 9.41 (s, 1H); 8.77 (d, 1H); 8.75 (s, 1H);8.36 (s, 1H); 7.90 (d, 1H); 7.71 (d, 2H); 7.60 (m, 1H); 7.40 (m, 1H);7.23 (m, 1H); 7.11 (d, 2H); 7.03 (m, 1H); 5.17 (s, 2H); 4.81 (s, 2H);3.85 (m, 2H); 3.76 (m, 2H); 3.10 (s, 3H); MS m/z 564 (M+1)⁺, 562 (m−1)⁻.

Example 16

[1003]

[1004]N-(1-benzyl-1H-indazol-5-yl)-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

[1005] Prepared according to Procedure D from5-(4-{4-(1-benzyl-1H-indazol-5-yl)-7-methoxy-6-quinazolinyl)-furan-2-carbaldehyde(0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). δ¹H NMR (400MHz, DMSO-d₆) 9.94(s, 1H), 8.76(s, 1H), 8.43(s, 1H), 8.13(d, 1H),8.12(s, 1H), 7.70(d, 1H), 7.66(m, 1H), 7.31 (m, 2H), 7.25(m, 4H),7.00(d, 1H), 6.46(d, 1H), 5.67(s, 2H), 4.05(s, 3H), 3.85(s, 2H), 3.27(t,2H), 3.00(s, 3H), 2.98(t, 2H); ESI-MS m/z 583(M+1).

Example 17

[1006]

[1007]6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-N-(4-{[3-(trifiuoromethyl)benzyl]oxy}phenyl)-4-quinazolinamine

[1008] Prepared according to Procedure D from5-(4-{4-(3-trifluoromethylbenzyloxy)anilino}-6-quinazolinyl)-furan-2-carbaldehyde(0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). ¹H NMR 300 MHz(DMSO-d6) 11.63 (bs, 1H); 9.88 (bs, 1H); 9.59 (bs, 1H); 8.88 (s, 1H);8.43 (d, 1H); 7.97 (d, 1H); 7.90-7.67 (m, 6H); 7.34 (d, 1H); 7.19 (d,2H); 6.89 (d, 1H); 5.30 (s, 2H); 4.45 (s, 2H); 3. 78 (m, 2H); 3.45 (m,2H, obscured by water peak); 3.19 (s, 3H); MS m/z 597 (M+1).

Example 18

[1009]

[1010]N-{3-fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

[1011] Prepared according to Procedure D from5-(4-{3-fluoro-4-(3-fluorobenzyloxy)anilino}-6-quinazolinyl)-furan-2-carbaldehyde(0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). ¹H NMR 400 MHz(DMSO-d6) 9.61 (bs, 2H); 9.28 (bs, 1H); 8.80 (s, 1H); 8.34 (d, 1H); 7.87(m, 2H); 7.59 (d, 1H); 7.44 (m, 1H); 7.2-7.38 (m, 4H); 7.18 (m, 1H);6.83 (s, 1H); 5.25 (s, 2H); 4.42 (s, 2H); 3.60 (m, 2H); 3.45 (m, 2H,obscured by water peak); 3.16 (s, 3H); MS m/z 565 (M+1).

Example 19

[1012]

[1013]N-{4-[(3-bromobenzyl)oxy]phenyl}-6-[5-(J[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

[1014] Prepared according to Procedure D from5-(4-{3-bromo-4-benzyloxyanilino}-6-quinazolinyl)-furan-2-carbaldehyde(0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). ¹H NMR 400 MHz(DMSO-d6) 11.78 (bs, 1H); 9.65 (bs, 1H); 9.39 (bs, 1H); 8.78 (s, 1H);8.37 (d, 1H); 7.90 (d, 1H); 7.66 (m, 3H); 7.53 (d, 1H); 7.42 (d, 1H);7.38 (m, 1H); 7.22 (s, 1H); 7.18 (d, 2); 6.82 (d, 1H); 5.18 (s, 2H);4.41 (s, 2H); 3.62 (m, 2H); 3.44 (m, 2H, obscured by water peak); 3.10(s, 3H); MS m/z 606, 608 (M+1).

Example 20

[1015]

[1016]N-[4-(benzyloxy)phenyl]-6-[3-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

[1017] Prepared according to Procedure D from5-(4-(4-benzyloxyanilino)-6-quinazolinyl)-furan-2-carbaldehyde (0.6equiv) and 2-methanesulphonyl-ethylamine(1 equiv). ¹HNMR 400MHz,(d6DMSO) 9.46(brs, 1H), 8.94 (s, 1H), 8.7 (s, 1H), 8.16 (d, 1H),7.96 (s, 1H), 7.88 (d, 1H), 7.67 (d, 2H), 7.5-7.2 (m, 5H), 7.07 (d, 2H),6.93 (s, 1H), 5.12 (s, 2H), 4.38 (brs, 2H), 3.59 (m, 2H), 3.46 (brs,2H), 3.09 (s, 3H); MS m/z 529 (M+1)

Example 21

[1018]

[1019]N-[1-(3-fluorobenzyl)-1H-indazol-5-yl]-6-[2-{[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine

[1020] Prepared according to Procedure F from6-iodo-(4-(3-fluorobenzyl)-1H-indazol-5-yl)quinazolin-4-ylamine (1equiv), 2-ethoxyvinyl-tributylstannane (1 equiv), N-bromosuccinimide (1equiv) andN-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide (1equiv). ¹H NMR (d₄ MeOH) d 9.44 (s, 1H), 8.76 (m, 2H), 8.36 (s, 1H),8.18 (s, 1H), 8.15, (s, 1H), 7.92 (d, 1H), 7.75 (m, 2H), 7.34 (m, 1H),7.04 (m, 2H), 6.92 (d, 1H), 5.71 (s, 2H), 4.80 (s, 2H), 3.82 (m, 2H),3.74 (m, 2H), 3.08 (s, 3H); MS m/z 588 (M+H+)

Example 22

[1021]

[1022]6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-N-[4-(benzenesulphonyl)phenyl]-4-quinazolinamine

[1023] Prepared according to Procedure D from5-(4-{4-(benzenesulphonyl)phenyl}-6-quinazolinyl)-furan-2-carbaldehyde(0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). ¹H NMR(DMSO-d6) 10.27 (s, 1H), 8.78 (s, 1H), 8.65 (s, 1H), 8.18-8.22 (m, 3H),7.97-8.01 (m, 4H), 7.86 (d, 1H), 7.62-7.72 (m, 3H), 7.10 (d, 1H), 6.51(d, 1H), 3.84 (s, 1H), 3.28 (t, 2H), 3.03 (s, 3H), 2.99 (t, 2H); m/z(M+1)⁺563.

Example 23

[1024]

[1025]6-[2-{[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-N-[4-(benzenesulphonyl)phenyl]-4-quinazolinamine

[1026] Prepared according to Procedure F from6-iodo-(4-(benzenesulphonyl)-phenyl)-quinazolin-4-ylamine (1 equiv),2-ethoxyvinyl-tributylstannane (1 equiv), N-bromosuccinimide (1 equiv)and N-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide(1 equiv). ¹H NMR 400 MHz (DMSO-d6) 9.80 (s, 1H); 8.87 (s, 1H); 8.65 (s,1H); 8.64 (s, 1H); 8.17 (s, 1H); 8.03 (s, 1H); 7.98 (m, 2H); 7.66 (m,5H); 4.73 (s, 2H); 3.68 (m, 2H); 3.55 (m, 2H); 3.12 (s, 3H); MS m/z 580(M+1)⁺, 578 (m−1)⁻.

Example 24

[1027]

[1028]6-[2-{[2-(methanesulphonyl)ethyl]amino}methyl)-1.3-thiazol-4-yl]-N-(4-{[3-(trifluoromethy)benzyl]oxy}phenyl)-4-quinazolinamine

[1029] Prepared according to Procedure F from6-iodo-(4-(3-trifluoromethylbenzyloxy)-phenyl)quinazolin-4-ylamine (1equiv), 2-ethoxyvinyl-tributylstannane (1 equiv), N-bromosuccinimide (1equiv) andN-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide (1equiv). ¹H NMR 400 MHz (CD₃OD) 9.40 (s, 1H); 8.75 (d, 1H); 8.73 (s, 1H);8.35 (s, 1H); 7.89 (d, 1H); 7.77 (s, 1H); 7.73 (m, 1H); 7.61 (m, 3H);7.52 (m, 1H); 7.14 (d, 2H); 5.24 (s, 2H); 4.82 (s, 2H); 3.85 (m, 2H);3.76 (m, 2H); 3.10 (s, 3H); MS m/z 614 (M+1)⁺, 612 (m−1)⁻.

Example 25

[1030]

[1031]N-{3-fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[2-{[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine

[1032] Prepared according to Procedure F from6-iodo-4-(1-benzyl-1H-indazol-5-yl)-quinazolin-4-ylamine (1 equiv),2-ethoxyvinyl-tributylstannane (1 equiv), N-bromosuccinimide (1 equiv)and N-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide(1 equiv). ¹H NMR 400 MHz (CD₃OD) 9.28 (s, 1H); 8.78 (s, 1H); 8.74 (d,1H); 8.31 (s, 1H); 7.90 (d, 1H); 7.74 (d, 1H); 7.63 (m, 1H); 7.54 (m,1H); 7.49 (m, 1H); 7.37 (m, 1H); 7.25 (m, 2H); 7.05 (m, 1H); 5.24 (s,2H); 4.77 (s, 2H); 3.81 (m, 2H); 3.72 (m, 2H); 3.10 (s, 3H); MS m/z 582(M+1)⁺, 580 (m−1)⁻

Example 26

[1033]

[1034]N-(1-benzyl-1H-indazol-5-yl)-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine

[1035] Prepared according to Procedure F from6-iodo-4-(1-benzyl-1H-indazol-5-yl)-quinazolin-4-ylamine (1 equiv),2-ethoxyvinyl-tributylstannane (1 equiv), N-bromosuccinimide (1 equiv)and N-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide(1 equiv). δ¹H NMR (d₄ MeOH) 9.37 (s, 1H), 8.74 (m, 2H), 8.33 (s, 1H),8.17 (s, 1H), 8.14, (s, 1H), 7.90 (d, 1H), 7.70 (m, 2H), 7.22 (m, 5H),5.69 (s, 2H), 4.78 (s, 2H), 3.81 (m, 2H), 3.74 (m, 2H), 3.09 (s, 3H); MSm/z 570 (M+H⁺).

Example 27

[1036]

[1037]N-(3-Fluoro-4-benzyloxyphenyl)-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-4-furyl]-4-quinazolinamine

[1038] Prepared according to Procedure D from5-(4-{3-fluoro-4-benzyloxyanilino}-6-quinazolinyl)-furan-2-carbaldehyde(0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). ¹H NMR 400 MHz(DMSO-d6) 8.83 (s, 1H); 8.35 (d, 1H); 7.89 (d, 1H); 7.83 (d, 1H); 7.59(d, 1H); 7.48-7.31 (m, 7H); 7.26 (s, 1H); 6.83 (d, 1H); 5.21 (s, 2H);4.42 (s, 2H); 3.60 (m, 2H); 3.44 (m, 2H, obscured by water peak); 3.12(s, 3H); MS m/z 547 (M+H⁺).

Example 28

[1039]

[1040]N-(3-Chloro-4-benzyloxyphenyl)-6-[5-{[2-(methanesulphonyl)ethyl]amino}methyl)-4-furyl]-4-quinazolinamine

[1041] Prepared according to Procedure D from5-(4-{3-chloro-4-benzyloxyanilino}-6-quinazolinyl)-furan-2-carbaldehyde(0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). ¹H NMR 400 MHz(DMSO-d6) 9.71 (bs, 2H); 9.45 (bs, 1H); 8.86 (s, 1H); 8.36 (d, 1H); 7.98(d, 1H); 7.90 (d, 1H); 7.74 (d, 1H); 7.49-7.44 (m, 2H); 7.40 (m, 2H);7.35-7.30 (m, 2H); 7.28 (d, 1H); 6.83 (d, 1H); 5.25 (s, 2H); 4.42 (s,2H); 3.62 (m, 2H); 3.44 (m, 2H); 3.12 (s, 3H); MS m/z 563 (M+H⁺).

Example 29

[1042]

[1043]N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

[1044] Prepared according to Procedure D from5-(4-{3-chloro-4-(3-fluorobenzyloxy)-anilino}-6-quinazolinyl)-furan-2-carbaldehyde(0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). ¹H NMR 400 MHz(DMSO-d6) 9.60 (bs, 1H); 9.32 (bs, 1H); !D 8.82 (bs, 1H); 8.34 (d, 1H);8.0 (s, 1H); 7.88 (d, 1H); 7.74 (d, 1H); 7.45 (m, 1H); 7.34-7.23 (m,4H); 7.17 (m, 1H); 6.83 (d, 1H); 5.27 (s, 2H); 4.42 (s, 2H); 3.59 (m,2H); 3.40 (m, 2H, obscured by waterpeak); 3.12 (s, 3H); MS m/z 581(M+H⁺).

Example 30

[1045]

[1046](4-Phenoxyphenyl)-(7-(2-(2-methanesulphonyl)ethylaminomethyl)thiazol-4-yl)-quinolin-4-yl)amine

[1047] A suspension of(4-(4-(4-phenoxy)anilino)-quinolin-7-yl)thiazole-2-carbaldehyde (0.05 g,0.14 mmol), sodium triacetoxyborohydride (0.1 2 g, 0.56 mmol),methanesulphonylethylamine (0.15 g, 1.2 mmol) and powdered 3 A molecularsieves in dichloromethane (6 ml) and glacial acetic acid (1 ml) wasstirred at room temperature (21° C.) overnight (18hrs) according toProcedure D. The crude reaction mixture was filtered through a SPEcolumn (SCX resin, 5 g, 25 ml), sequentially washed with methanol (2×1 0ml) and 10% ammonia in methanol (3×1 0 ml) and the product isolated as apale yellow gum. Trituration with water (5 ml) and drying of theresultant solid over phosphorus pentoxide at 60° C. under vacuum for5hrs yielded the purified product as a pale yellow solid (0.031 g, 49%);δH [²H₆] DMSO 8.80(1H, s), 8.25(3H, m), 8.10(1H, s), 7.90(1H, d),7.20(4H, 2d), 6.85(5H, m), 6.60(1H, d), 3.95(2H, d), 2.90(7H, m); m/z531 (M+1)⁺.

Example 31

[1048]

[1049](4-Phenoxyphenyl)-(7-(4-(2-methanesulphonyl)ethylaminomethyl)thiazol-5-yl)-quinolin-4-yl)amine

[1050] 4-(4-Phenoxyanilino) 7-(4-formyl thiazol-5-yl) quinoline(50 mg,0.118 mmol), methanesulphonylethylamine (50 mg) and molecular seives(4A, 2 large spatula tips) were stirred in a mixture of dichloromethane(6 ml) and acetic acid (1 ml) at room temperature for 2hr (Procedure D).Sodium triacetoxyborohydride (0.12 g, 0.567 mmol) was then added and thereaction was stirred at room temp for 18hr. The reaction mixture wasadded to a 5 g SCX cartridge and washed with methanol, the product waseluted with 10% methanolic ammonia. The product was triturated withwater to give a beige solid (39.7 mg); δH [²H₆] DMSO 9.32 (1H, s), 9.22(1H, s), 8.64 is: (2H, m), 8.19 (1H, s), 7.87 (1H, d), 7.56 (4H, m),7.27 (6H, m), 7.02 (1H, d), 4.07 (2H, s), 3.42 (2H, t), 3.14 (5H, m);m/z531.

Example 32

[1051]

[1052](4-Phenoxyphenyl)-(7-(5-(2-(methanesulphonyl)ethylaminomethyl)furan-2-yl)-quinolin-4-yl)amine

[1053] 5-(4-(4-phenoxyphenylamino)-quinolin-7-yl)furan-2-carbaldehyde(0.05 g) was reacted with 2-(methanesulphonyl)ethylamine (0.075 g)according to procedure D. Acidification with acetic acid (0.5 ml)followed by purification using a ion-exchange (SCX) Bond Elut™cartridge, eluting with methanol-ammonia (9:1), concentration andtrituration with diethylether afforded an off-white solid; δH [²H₆]DMSO8.44 (1H, d), 8.41 (1H, d), 8.11 (1H, s), 7.85 (1H, d), 7.44-7.35 (4H,m), 7.18-7.03 (6H, m), 6.79 (1H, d), 6.47 (1H, d), 3.82 (2H, s), 3.01(2H, t); m/z 514 (M+1)⁺.

Example 33

[1054]

[1055]6-[5-({[2-(Methanesulphonyl)ethyl]amino}methyl)-2-furyl]-7-methoxy-N-(4benzenesulphonyl)phenyl-4-quinazolinamine

[1056] Prepared according to Procedure D from5-(7-methoxy-4-(4-benzenesulphonyl)phenylamino-quinazolin-6-yl)furan-2-carbaldehydehydrochloride (0.6 equiv) and 2-methanesulphonyl (1 equiv). δ¹H NMR (400MHz, DMSO-d₆) 10.23 (s, 1H), 8.76(s, 1H), 8.59 (s, 1H), 8.14 (d, 2H),7.96 (m, 4H), 7.59-7.71 (m, 3H), 7.33 (s, 1H), 7.03 (d, 1H), 6.47 (d,1H), 4.06 (s, 3H), 3.86 (s, 2H), 3.27 (t, 2H), 3.00 (s, 3H), 2.98 (t,2H). ESI-MS m/z 593(M+1).

Example 34

[1057]

[1058]N-[4-(Benzyloxy)phenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

[1059] Prepared according to Procedure D from a mixture of5-(4-(4-benzyloxy-phenylamino)-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehydehydrochloride (0.13 grams) in 1,2-dichloroethane (3 ml),diisopropylethylamine (65 mg), acetic acid (45 mg),2-methanesulphonylethylamine (0.125 grams), and sodiumtriacetoxyborohydride (0.27 grams). The mixture was stirred for 18hours. The reaction mixture was quenched with methanol (3 ml) and pouredinto a separatory funnel containing aqueous saturated sodium hydrogencarbonate (100 ml) and ethyl acetate (100 ml). The mixture wasextracted. The organic layer was washed with water. The organic layerwas dried over magnesium sulfate, filtered, and concentrated. Theresidue was treated with ethyl acetate/hexanes and collected byfiltration (0.083 g, 61% yield). δ¹H NMR (400 MHz, DMSO-d₆) 9.98(s, 1H),8.83(d, 1H), 8.44(s, 1H), 7.58(m, 3H), 7.44(m, 2H), 7.37(m, 2H), 7.31(m,1H), 7.03(d, 1H), 6.91(m, 1H), 6.5(d, 1H), 5.1(s, 2H), 3.84(s, 1H),3.25(m, 2H), 2.99(s, 3H), 2.96(m, 2H). ESI-MS m/z 545(M−1).

Example 35

[1060]

[1061] N-(1-Benzyl-1H-indazol-5-yl)-7-fluoro-[5-({[2(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

[1062] Prepared according to Procedure D from 5-(4-(1-Benzyl-1H-indazol-5-ylamino)-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde(0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). δ¹H NMR (400MHz, DMSO-d₆) 10.16(s, 1H), 8.91 (d, 1H), 8.46(s, 1H), 8.11(s, 2H),7.65(m, 3H), 7.26(m, 5H), 6.93(m, 1H), 6.54(d, 2H), 5.65(s, 2H), 3.89(s,2H), 3.28(m, 2H), 2.99(m, 5H). ESI-MS m/z 569(M−1).

Example 36

[1063]

[1064]N-[4-(Phenylsulphonyl)phenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

[1065] Prepared according to Procedure D from5-(4-(4-Phenyzsulphonylphenylamino)-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde(0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). ¹H NMR (400MHz, DMSO-d₆) δ: 10.38(s, 1H), 8.87(d, 1H), 8.62(s, 1H), 8.11 (d, 2H),7.95(m, 4H), 7.63(m, 4H), 6.94(m, 1H), 6.51 (d, 1H), 3.84(s, 2H),3.25(m, 2H), 2.98(s, 3H), 2.95(m, 2H). ESI-MS m/z 579(M−1).

Example 37

[1066]

[1067]N-(3-Trifluoromethyl-4-benzyloxyphenyl)-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-4-furyl]-4-quinazolinamine

[1068] The mixture of5-(4-(4-benzyloxy-3-trifluoromethylphenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde(211 mg, 0.40 mmol), 2-methanesulphonyl-ethylamine (99 mg, 2.0 mmol),acetic acid (0.5 ml) in dichloromethane (15 ml) was stirred at roomtemperature for 1.5 hours then was heated to reflux for 1 hour. Themixture was cooled to 0° C. with ice bath. Sodium cyanoborohydride (50mg, 0.8 mmol) was added at 0° C. The reaction mixture then was stirredat room temperature for 1 hour. Diluted with ethyl acetate (50 ml), thenquenched with saturated sodium bicarbonate solution slowly. Extractedwith ethyl acetate and the combined organic extracts were washed withbrine, dried over MgSO₄ and concentrated in vacuo. Purification of theresulting residue was accomplished using flash chromatography on silicagel with 2% methanol in ethyl acetate which afforded a yellow solid(0.10 g, 43% yield). H¹ NMR (400 MHz, DMSO).δ10.0 (s, 1H), 8.7 (s, 1H),8.5 (s, 1H), 8.1 (d, 1H), 8.1 (s, 2H), 7.8 (d, 1H), 7.4 (m, 5H), 7.3 (m,1H), 7.0 (d, 1H), 6.5 (d, 1H), 5.3 (s, 2H), 3.8 (s, 2H), 3.2 (m, 2H),3.0 (s, 3H), 2.9 (m, 2H). ESI-MS m/z 597 (M+H)⁺.

[1069] Further Examples

[1070] The compounds in Lists 1 to 48 above and their hydrochloridesalts, if appropriate, are prepared by analogous techniques using theappropriate starting materials.

[1071] Biological Data

[1072] Compounds of the present invention were tested for proteintyrosine kinase inhibitory activity in substrate phosphorylation assaysand cell proliferation assays.

[1073] Substrate Phosphorylation Assay

[1074] The substrate phosphorylation assays use baculovirus expressed,recombinant constructs of the intracellular domains of c-erbB-2 andc-erbB-4 that are constitutively active and EGFr isolated fromsolubilised A431 cell membranes. The method measures the ability of theisolated enzymes to catalyse the transfer of the g-phosphate from ATPonto tyrosine residues in a biotinylated synthetic peptide(Biotin-GluGluGluGluTyrPheGluLeuVal). Substrate phosphorylation wasdetected following either of the following two procedures: a.) c-ErbB-2,c-ErbB4 or EGFr were incubated for 30 minutes, at room temperature, with10 mM MnCl₂, 10 mM ATP, 5 mM peptide, and test compound (diluted from a5 mM stock in DMSO, final DMSO concentration is 2%) in 40 mM HEPESbuffer, pH 7.4. The reaction was stopped by the addition of EDTA (finalconcentration 0.15 mM) and a sample was transferred to astreptavidin-coated 96-well plate. The plate was washed and the level ofphosphotyrosine on the peptide was determined using a Europium-labelledantiphosphotyrosine antibody and quantified with a time-resolvedfluorescence technique. b.) ErbB2 was incubated for 50 minutes at roomtemperature with 15 mM MnCl_(2,2) mM ATP, 0.25 mCi [γ-³³P] ATP/well, 5mM peptide substrate, and test compound (diluted from a 10 mM stock inDMSO, final DMSO concentration is 2%) in 50 mM MOPS pH 7.2. The reactionwas terminated by the addition of 200 ml of PBS containing 2.5 mg/mlstreptavidin-coated SPA beads (Amersham Inc.), 50 mM ATP, 10 mM EDTA and0.1%TX-100. The microtitre plates were sealed and SPA beads were allowedto settle for at least six hours. The SPA signal was measured using aPackard Topcount 96-well plate scintillation counter (Packard InstrumentCo., Meriden, Conn.).

[1075] The results are shown in Tables 1 A (examples 1 to 7) and 1 B(examples 8 to 29 and 33 to 37) as the IC₅₀ values. TABLE 1A SubstratePhosphorylation Example erbB2 - assay (b) EGF-r - assay (a) 1 +++ +++ 2+++ +++ 3 +++ +++ 4 ++ +++ 5 +++ +++ 6 ++ 7 +++ +++

[1076] TABLE 1B Substrate Phosphorylation Example erbB2 - assay (b) 8+++ 9 +++ 10 +++ 11 +++ 12 ++ 13 ++ 14 +++ 15 +++ 16 +++ 17 +++ 18 +++19 +++ 20 +++ 21 +++ 22 +++ 23 +++ 24 +++ 25 +++ 26 +++ 27 +++ 28 +++ 29+++ 33 +++ 34 +++ 35 +++ 36 +++ 37 +++ IC₅₀ values Symbol <0.10 μM +++0.10-1.0 μM ++ 1.0-10.0 μM + >10.0 μM — Not determined ND

[1077] Cellular Assays:

[1078] Methylene Blue Growth Inhibition Assay

[1079] Human breast (BT474), head and neck (HN5) and gastric tumor (N87)cell lines were cultured in low glucose DMEM (Life Technologies12320-032) containing 10% fetal bovine serum (FBS) at 37° C. in ahumidified 10% CO₂, 90% air incubator. The SV40 transformed humanmammary epithelial cell line HB4a was transfected with either humanH-ras cDNA (HB4a r4.2) or the human c-erbB2 cDNA (HB4a c5.2). The HB4aclones were cultured in RPMI containing 10% FBS, insulin (5 μg/ml),hydrocortisone (5 μg/ml), supplemented with the selection agenthygromycin B (50μg/ml). Cells were harvested using trypsin/EDTA, countedusing a haemocytometer, and plated in 100 ml of the appropriate media,at the following densities, in a 96-well tissue culture plate (Falcon3075): BT474 10,000 cells/well, HN53,000 cells/well, N87 10,000cells/well, HB4a c5.2 3,000 cells/well, HB4a r4.2 3,000 cells/well. Thenext day, compounds were diluted in DMEM containing 100 mg/mlgentamicin, at twice the final required concentration, from 10 mM stocksolutions in DMSO. 100 ml/well of these dilutions were added to the 100ml of media currently on the cell plates. Medium containing 0.6% DMSOwas added to control wells. Compounds diluted in DMEM were added to allcell lines, including the HB4a r4.2 and HB4a c5.2 cell lines. The finalconcentration of DMSO in all wells was 0.3%. Cells were incubated at 37°C., 10% CO₂ for 3 days. Medium was removed by aspiration. Cell biomasswas estimated by staining cells with 100 per well methylene blue (SigmaM9140, 0.5% in 50:50 ethanol:water), and incubation at room temperaturefor at least 30 minutes. Stain was removed, and the plates rinsed undera gentle stream of water, and air-dried. To release stain from the cells100 μl of solubilization solution was added (1% N-lauroyl sarcosine,Sodium salt, Sigma L5125, in PBS), and plates were shaken gently forabout 30 minutes. Optical density at 620 nM was measured on a microplatereader. Percent inhibition of cell growth was calculated relative tovehicle treated control wells. Concentration of compound that inhibits50% of cell growth (IC₅₀) was interpolated using nonlinear regression(Levenberg-Marquardt) and the equation, y=V_(max)*(1−(x/(K+x)))+Y2,where “K” was equal to the IC₅₀.

[1080] Table 2 illustrates the inhibitory activity of compounds of thepresent invention as IC₅₀ values in, μM against a range of tumor celllines. TABLE 2 Cell Proliferation HB4a HB4a Example erbB2 ras BT474 HN5N87  1 +++ + +++ +++ +++  2 +++ + +++ +++ +++  3 +++ + +++ +++ +++  4+++ − +++ +++ +++  5 +++ − +++ +++ +++  6 +++ + +++ +++ +++  7 +++ +++++ +++ +++  8 +++ ++ +++ +++ +++  9 +++ ++ +++ +++ +++ 10 +++ ++ ++++++ +++ 11 +++ − +++ +++ +++ 12 +++ − +++ ++ +++ 13 ++ − ++ + ++ 14 +++− +++ +++ +++ 15 +++ − +++ +++ +++ 16 +++ ++ +++ +++ +++ 17 ++ ++ +++ ++++ 18 +++ ++ +++ +++ +++ 19 +++ − +++ +++ +++ 20 +++ − +++ ++ +++ 21 +++++ +++ +++ +++ 22 +++ + +++ +++ +++ 23 +++ + +++ +++ +++ 24 ++ − ++ +++++ 25 +++ − +++ +++ +++ 26 +++ ++ +++ +++ +++ 27 +++ ++ +++ +++ +++ 28+++ + +++ +++ +++ 29 +++ − +++ +++ +++ 33 +++ +++ +++ +++ +++ 34 +++ −+++ +++ +++ 35 +++ + +++ +++ +++ 36 ++ − ++ ++ ++ 37 +++ + +++ +++ +++IC₅₀ value Symbol <5 μM +++ 5-25 μM ++ 25-50 μM + >50 μM − Notdetermined ND

[1081] Major Metabolites:

[1082] Liver S-9 homogenates (5 mg/mL protein concentration) fromprepared pooled male Sprague Dawley rat livers and pooled human livers(XenoTech, LLC, Kansas City, Kans.) were incubated in 96-wellpolypropylene plates with representative examples selected from examples1 to 40 (10 μM) in a total volume of 0.5 mL. Stock solutions of thesecompounds were prepared in DMSO at a concentration of 1 mM to maintain a<1% final DMSO concentration for each reaction. Enzymatic incubationscontained cofactors (5.71 mM NADPH, 7.14 mM glucose-6-phosphate, 7.14 mMUDPGA, 47.1 mM potassium chloride, and 11.4 mM magnesium chloride in 0.1M potassium phosphate buffer, pH 7.4). Control samples were aspiratedfrom the reaction samples at time zero and placed immediately into 2volumes of ice-chilled acetonitrile. Sample reaction plates wereincubated for 60 min in a shaker incubator maintained at 37° C. suppliedwith O₂. Reactions were terminated by addition of 2 volumes ofice-chilled acetonitrile. All samples were vortexed and centrifuged at2000× g for 10 min. The supernatant was removed and analyzed by LC-MS.The metabolite identification work was done by using reversed-phase HPLCcoupled with ion-trap mass spectroscopy.

[1083] For example:

[1084]N-[4-(Benzyloxy)phenyl]-6-[4-(aminomethyl)-2-furyl]-4-quinazolinamine

[1085] Prepared according to Procedure D and identified as a majormetabolite ofN-[4-(benzyloxy)phenyl]-6-[4-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinaminein ¹HNMR 300 MHz, CDCl₃ 8.69(s, 1H), 8.11 (s, 1H), 8.02 (d, 1H), 7.88(d, 1H), 7.61 (d, 2H), 7.5-7.2 (m, 7H), 7.05 (d, 2H), 6.83 (s, 1H), 5.10(s, 2H), 3.82 (s, 2H); MS m/z 423 (M+1).

[1086] Thus, particular compounds of interest as metabolites (either asisolated compounds or compounds in vivo) are compounds of formula(XVII):

[1087] in which Ar, Y, V, X and U are as defined above; all possiblepreferments for these groups as defined above are applicable.

[1088] Compounds of formula (XII) of special interest include:

[1089]4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-(aminomethyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[1090](4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-(aminomethyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[1091](4-Benzenesulphonyl-phenyl)-(6-(5-(aminomethyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[1092](4-Benzyloxy-phenyl)-(6-(3-(aminomethyl)phenyl-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[1093](4-Benzyloxy-phenyl)-(6-(5-(aminomethyl)-furan-2-yl)-quinazolin-4-yl)-amine;

[1094](4-(3-Fluorobenzyloxy-phenyl)-(6-(4-(aminomethyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

[1095](4-Benzyloxy-phenyl)-(6-(2-(aminomethyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;

[1096]N-{4-[(3-Fluorobenzyl)oxy]phenyl}-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine;

[1097]N-{4-[(3-Fluorobenzyl)oxy]-3-methoxyphenyl}-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine;

[1098]N-[4-(Benzyloxy)phenyl]-7-methoxy-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine;

[1099]N-[4-(Benzyloxy)phenyl]-6-[4-(aminomethyl)-2-furyl]-4-quinazolinamine;

[1100]N-{4-[(3-Fluorobenzyl)oxy]-3-methoxyphenyl}-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[1101]N-{4-[(3-Bromobenzyl)oxy]phenyl}-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[1102]N-{4-[(3-Fluorobenzyl)oxy]phenyl}-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[1103]N-[4-(Benzyloxy)-3-fluorophenyl]-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[1104]N-(1-Benzyl-1H-indazol-5-yl)-7-methoxy-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine;

[1105]6-[5-(aminomethyl)-2-furyl]-N-(4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)-4-quinazolinamine;

[1106]N-{3-Fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine;

[1107]N-{4-[(3-Bromobenzyl)oxy]phenyl}-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine;

[1108]N-[4-(Benzyloxy)phenyl]—6-[-(aminomethyl)-2-furyl]-4-quinazolinamine;

[1109]N-[1-(3-Fluorobenzyl)-1H-indazol-5-yl]-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[1110]6-[5-(Aminomethyl)-2-furyl]-N-[4-(benzenesulphonyl)phenyl]-4-quinazolinamine;

[1111]6-[2-(Aminomethyl)-1,3-thiazol-4-yl]-N-[4-(benzenesulphonyl)phenyl]-4-quinazolinamine;

[1112]6-[2-(Aminomethyl)-1,3-thiazol-4-yl]-N-(4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)-4-quinazolinamine

[1113]N-{3-Fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[1114]N-(1-Benzyl-1H-indazol-5-yl)-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[1115]N-(3-Fluoro-4-benzyloxyphenyl)-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[1116]N-(3-Chloro-4-benzyloxyphenyl)-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-4-quinazolinamine;

[1117]N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine;

[1118](4-Phenoxyphenyl)-(7-(2-(aminomethyl)-thiazol-4-yl)-quinolin-4-yl)amine;

[1119](4-Phenoxyphenyl)-(7-(4-(aminomethyl)-thiazol-5-yl)-quinolin-4-yl)amine;

[1120](4-Phenoxyphenyl)-(7-(5-(aminomethyl)-furan-2-yl)-quinolin-4-yl)amine;

[1121]6-[5-(Aminomethyl)-2-furyl]-7-methoxy-N-(4-phenylsulphonyl)phenyl-4-quinazolinamine;

[1122]N-[4-(Benzyloxy)phenyl]-7-fluoro-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine;

[1123]N-(1-Benzyl-1H-indazol-5-yl)-7-fluoro-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine;

[1124]N-[4-(Benzenesulphonyl)phenyl]-7-fluoro-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine;

[1125]N-(3-Trifluoromethyl-4-benzyloxyphenyl)-6-[5-(aminomethyl)-4-furyl]-4-quinazolinamine;

[1126] and salts or solvates thereof, particularly pharmaceuticallyacceptable salts thereof.

We claim:
 1. A compound of the formula:

and salts or solvates thereof.
 2. A pharmaceutical formulation,comprising: the compound of claim 1 or a pharmaceutically acceptablesalt or solvate thereof together with one or more pharmaceuticallyacceptable carriers, diluents, or excipients.
 3. A method of treating asusceptible cancer in a human or animal subject mammal, comprisingadministering to said subject an effective amount of a compound asclaimed in claim
 1. 4. A method as claimed in claim 1, wherein thesusceptible cancer is a susceptible breast cancer.
 5. A method asclaimed in claim 1, wherein the susceptible cancer is a susceptiblenon-small cell lung cancer.
 6. A method as claimed in claim 1, whereinthe susceptible cancer is a susceptible ovarian cancer.
 7. A method asclaimed in claim 1, wherein the susceptible cancer is a susceptiblestomach cancer.
 8. A method as claimed in claim 1, wherein thesusceptible cancer is a susceptible pancreatic cancer.
 9. A method asclaimed in claim 1, wherein the susceptible cancer is a susceptible headand neck cancer.
 10. A method as claimed in claim 1, wherein thesusceptible cancer is a susceptible cancer characterized by expressionor over-expression of EGFR.
 11. A method as claimed in claim 1, whereinthe susceptible cancer is a susceptible cancer characterized byexpression or over-expression of erbB-2.
 12. A method as claimed inclaim 1, wherein the susceptible cancer is a susceptible cancercharacterized by expression or over-expression of EGFR and erbB-2.